Fumagillol spirocyclic compounds and fused bicyclic compounds and methods of making and using same

ABSTRACT

Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/922,378, filed Mar. 15, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/827,074, filed Nov. 30, 2017, which is acontinuation of International Patent Application NumberPCT/US2016/046515, filed Aug. 11, 2016, which claims the benefit of, andpriority to, Chinese Patent Application Number 201510490559.1, filedAug. 11, 2015, and U.S. Provisional Patent Application No. 62/210,102,filed Aug. 26, 2015, the contents of each of which are herebyincorporated by reference in their entirety.

BACKGROUND

Over 1.1 billion people worldwide are reported to be overweight. Obesityis estimated to affect over 90 million people in the United Statesalone. Twenty-five percent of the population in the United States overthe age of twenty is considered clinically obese. While being overweightor obese presents problems (for example restriction of mobility,discomfort in tight spaces such as theater or airplane seats, socialdifficulties, etc.), these conditions, in particular clinical obesity,affect other aspects of health, i.e., diseases and other adverse healthconditions associated with, exacerbated by, or precipitated by beingoverweight or obese. The estimated mortality from obesity-relatedconditions in the United States is over 300,000 annually (O'Brien et al.Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science,280:1371).

There is no curative treatment for being overweight or obese.Traditional pharmacotherapies for treating an overweight or obesesubject, such as serotonin and noradrenergic re-uptake inhibitors,noradrenergic re-uptake inhibitors, selective serotonin re-uptakeinhibitors, intestinal lipase inhibitors, or surgeries such as stomachstapling or gastric banding, have been shown to provide minimalshort-term benefits or significant rates of relapse, and have furthershown harmful side-effects to patients.

MetAP2 encodes a protein that functions at least in part byenzymatically removing the amino terminal methionine residue fromcertain newly translated proteins such as glyceraldehyde-3-phosphatedehydrogenase (Warder et al. (2008) J. Proteome Res. 7:4807). Increasedexpression of the MetAP2 gene has been historically associated withvarious forms of cancer. Molecules inhibiting the enzymatic activity ofMetAP2 have been identified and have been explored for their utility inthe treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis,leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34).Notably, inhibition of MetAP2 activity in obese and obese-diabeticanimals leads to a reduction in body weight in part by increasing theoxidation of fat and in part by reducing the consumption of food(Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).

Such MetAP2 inhibitors may be useful as well for patients with excessadiposity and conditions related to adiposity including type 2 diabetes,hepatic steatosis, and cardiovascular disease (via e.g. amelioratinginsulin resistance, reducing hepatic lipid content, and reducing cardiacworkload). Accordingly, compounds capable of modulating MetAP2 areneeded to address the treatment of obesity and related diseases as wellas other ailments favorably responsive to MetAP2 modulator treatment.

SUMMARY

The present disclosure provides, for example, compounds which may bemodulators of MetAP2, and their use as medicinal agents, processes fortheir preparation, and pharmaceutical compositions containing them as anactive ingredient both alone or in combination with other agents, aswell as provides for their use as medicaments and/or in the manufactureof medicaments for the inhibition of MetAP2 activity in warm-bloodedanimals such as humans. In particular this disclosure relates tocompounds useful for the treatment of obesity, type 2 diabetes, andother obesity-associated conditions. Also provided are pharmaceuticalcompositions comprising at least one disclosed compound and apharmaceutically acceptable carrier.

For example, provided herein are compounds represented by Formula I orFormula Ia and pharmaceutically acceptable salts, stereoisomers, esters,and prodrugs thereof:

wherein:

is a single or double bond; and A, X, Y, m, n, R¹, and R² are describedbelow.

Also provided herein is a pharmaceutically acceptable compositioncomprising a disclosed compound (e.g., of Formula I or Ia) and apharmaceutically acceptable excipient.

Methods of treating and/or controlling obesity are contemplated herein,comprising administering to a patient in need thereof an effectiveamount of a disclosed compound (e.g., of Formula I or Ia). In anembodiment, a method of inducing weight loss in a patient in needthereof is provided, comprising administering to said patient aneffective amount of a disclosed compound (e.g., of Formula I or Ia). Inanother embodiment, a method of substantially preventing weight gain ina patient in need thereof is provided comprising administering to saidpatient an effective amount of a disclosed compound (e.g., of Formula Ior Ia).

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentdisclosure, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and as understood by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkoxyalkyl” as used herein refers to a straight or branchedalkyl group attached to oxygen, attached to a second straight orbranched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groupsinclude, but are not limited to, alkoxyalkyl groups in which each of thealkyl groups independently contains 1-6 carbon atoms, referred to hereinas C₁₋₆alkoxy-C₁₋₆alkyl. Exemplary alkoxyalkyl groups include, but arenot limited to methoxymethyl, 2-methoxyethyl, 1-methoxyethyl,2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl etc.

The term “alkyoxycarbonyl” as used herein refers to a straight orbranched alkyl group attached to oxygen, attached to a carbonyl group(alkyl-O—C(O)—). Exemplary alkoxycarbonyl groups include, but are notlimited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred toherein as C₁₋₆alkoxycarbonyl. Exemplary alkoxycarbonyl groups include,but are not limited to, methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, etc.

The term “alkenyloxy” used herein refers to a straight or branchedalkenyl group attached to oxygen (alkenyl-O—). Exemplary alkenyloxygroups include, but are not limited to, groups with an alkenyl group of3-6 carbon atoms, referred to herein as C₃₋₆alkenyloxy. Exemplary“alkenyloxy” groups include, but are not limited to allyloxy,butenyloxy, etc.

The term “alkynyloxy” used herein refers to a straight or branchedalkynyl group attached to oxygen (alkynyl-O). Exemplary alkynyloxygroups include, but are not limited to, groups with an alkynyl group of3-6 carbon atoms, referred to herein as C₃₋₆alkynyloxy. Exemplaryalkynyloxy groups include, but are not limited to, propynyloxy,butynyloxy, etc.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbonatoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkylcarbonyl” as used herein refers to a straight or branchedalkyl group attached to a carbonyl group (alkyl-C(O)—). Exemplaryalkylcarbonyl groups include, but are not limited to, alkylcarbonylgroups of 1-6 atoms, referred to herein as C₁₋₆alkylcarbonyl groups.Exemplary alkylcarbonyl groups include, but are not limited to, acetyl,propanoyl, isopropanoyl, butanoyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groupsinclude, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms,referred to herein as C₃₋₆cycloalkoxy groups. Exemplary cycloalkoxygroups include, but are not limited to, cyclopropoxy, cyclobutoxy,cyclohexyloxy, etc

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl orC₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur. Where possible, said heteroaryl ring may be linkedto the adjacent radical though carbon or nitrogen. Examples ofheteroaryl rings include but are not limited to furan, thiophene,pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole,triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to e.g. saturated or partially unsaturated, 4-10 membered ringstructures, or e.g. 4-6 membered saturated ring structures, includingbridged or fused rings, and whose ring structures include one to threeheteroatoms, such as nitrogen, oxygen, and sulfur. Where possible,heterocyclyl rings may be linked to the adjacent radical through carbonor nitrogen. Examples of heterocyclyl groups include, but are notlimited to, pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

The term “heterocyclyloxy” as used herein refers to a heterocyclyl groupattached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl groupattached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical—OH.

The term “oxo” as used herein refers to the radical ═O.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the present disclosure canbe administered to a mammal, such as a human, but can also beadministered to other mammals such as an animal in need of veterinarytreatment, e.g., domestic animals (e.g., dogs, cats, and the like), farmanimals (e.g., cows, sheep, pigs, horses, and the like) and laboratoryanimals (e.g., rats, mice, guinea pigs, and the like). The mammaltreated in the methods of the present disclosure is desirably a mammalin which treatment of obesity or weight loss is desired. “Modulation”includes antagonism (e.g., inhibition), agonism, partial antagonismand/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system or animal, (e.g.mammal or human) that is being sought by the researcher, veterinarian,medical doctor or other clinician. The compounds of the presentdisclosure are administered in therapeutically effective amounts totreat a disease. Alternatively, a therapeutically effective amount of acompound is the quantity required to achieve a desired therapeuticand/or prophylactic effect, such as an amount which results in weightloss.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts, particularly calcium, magnesium, sodium,lithium, zinc, potassium, and iron salts. Compounds included in thepresent compositions that include a basic or acidic moiety may also formpharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may contain one or more chiral centersand, therefore, exist as stereoisomers. The term “stereoisomers” whenused herein consist of all enantiomers or diastereomers. These compoundsmay be designated by the symbols “(+),” “(−),” “R” or “S,” depending onthe configuration of substituents around the stereogenic carbon atom,but the skilled artisan will recognize that a structure may denote achiral center implicitly. The present disclosure encompasses variousstereoisomers of these compounds and mixtures thereof. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a

carbon-carbon double bond. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclicring and therefore, exist as geometric isomers resulting from thearrangement of substituents around the ring. The arrangement ofsubstituents around a carbocyclic or heterocyclic ring are designated asbeing in the “Z” or “E” configuration wherein the terms “Z” and “E” areused in accordance with IUPAC standards. Unless otherwise specified,structures depicting carbocyclic or heterocyclic rings encompass both“Z” and “E” isomers. Substituents around a carbocyclic or heterocyclicrings may also be referred to as “cis” or “trans”, where the term “cis”represents substituents on the same side of the plane of the ring andthe term “trans” represents substituents on opposite sides of the planeof the ring. Mixtures of compounds wherein the substituents are disposedon both the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diasteriomers of compounds of the presentdisclosure can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the presentdisclosure embrace both solvated and unsolvated forms. In oneembodiment, the compound is amorphous. In one embodiment, the compoundis a single polymorph. In another embodiment, the compound is a mixtureof polymorphs. In another embodiment, the compound is in a crystallineform.

The present disclosure also embraces isotopically labeled compounds ofthe disclosure which are identical to those recited herein, except thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe present disclosure include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Forexample, a compound of the disclosure may have one or more H atomreplaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present disclosurecan generally be prepared by following procedures analogous to thosedisclosed in the examples herein by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound of the present disclosure or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁₋₈)alkyl, (C₂₋₁₂)alkylcarbonyloxymethyl,1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a disclosed compound contains an alcohol functional group,a prodrug can be formed by the replacement of the hydrogen atom of thealcohol group with a group such as (C₁₋₆)alkylcarbonyloxymethyl,1-((C₁₋₆)alkylcarbonyloxy)ethyl,1-methyl-1-((C₁₋₆)alkylcarbonyloxy)ethyl (C₁₋₆)alkoxycarbonyloxymethyl,N—(C₁₋₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkylcarbonyl,α-amino(C₁₋₄)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl,or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where eachα-aminoalkylcarbonyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

If a compound of the present disclosure incorporates an amine functionalgroup, a prodrug can be formed, for example, by creation of an amide orcarbamate, an N-alkylcarbonyloxyalkyl derivative, an(oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.In addition, a secondary amine can be metabolically cleaved to generatea bioactive primary amine, or a tertiary amine can metabolically cleavedto generate a bioactive primary or secondary amine. For examples, seeSimplicio, et al., Molecules 2008, 13, 519 and references therein.

I. Fumagillol Compounds

In one aspect, the present disclosure provides compounds of Formula I orIa:

wherein:

is a single or double bond;

Y is a bond or NR^(a);

X is N or CR^(N); wherein X is N when Y is a bond and X is CR^(N) when Yis NR^(a);

n is 0 or 1;

m is 1 or 2;

Ring A may be optionally substituted by one or two substituents eachindependently selected from the group consisting of halogen, hydroxyl,C₁₋₃alkyl and C₁₋₃alkoxy, wherein C₁₋₃alkyl and C₁₋₃alkoxy mayoptionally be substituted by one or more fluorine atoms or a substituentselected from the group consisting of cyano, hydroxyl, andN(R^(a)R^(b));

R¹ and R², together with the carbon or carbons to which they areattached, form a 4-6 membered saturated heterocyclic ring B having oneor two heteroatoms selected from the group consisting of O, S(O)_(w)(wherein w is 0, 1 or 2) and NR^(h) or form a 3-6 membered saturatedcarbocyclic ring B; wherein the heterocyclic or carbocyclic ring B mayoptionally be substituted on a free carbon by one or two substituentseach independently selected from the group consisting of halogen,hydroxyl, oxo, C₁₋₃alkyl, C₁₋₃alkoxy, —C(O)—NR^(i)R^(j),—C(O)—N(R^(a))—C₁₋₆alkylene-NR^(i)R^(j), —C₁₋₆alkylene-NR^(i)R^(j),—C₁₋₆alkylene-O—C(O)—NR^(i)R^(j), and —O—C(O)—NR^(i)R^(j); whereinC₁₋₃alkyl, C₁₋₃alkoxy, —C(O)—NR^(i)R^(j),—C(O)—N(R^(a))—C₁₋₆alkylene-NR^(i)R^(j), —C₁₋₆alkylene-NR^(i)R^(j),—C₁₋₆alkylene-O—C(O)—NR^(i)R^(j), and —O—C(O)—NR^(i)R^(j) may optionallybe substituted by one or more fluorine atoms or a group selected fromcyano, hydroxyl, or N(R^(a)R^(b));

R^(i) and R^(j) are selected independently for each occurrence from thegroup consisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,heterocyclyl and heterocyclylcarbonyl; wherein C₁₋₆alkyl, C₂₋₆alkenyland C₃₋₆cycloalkyl may be optionally substituted by one or moresubstituents independently selected from the group consisting offluorine, hydroxyl, cyano, R^(a)R^(b)N—, R^(a)R^(b)N-carbonyl- andC₁₋₃alkoxy; and wherein heterocyclyl and heterocyclylcarbonyl may beoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, halo-C₁₋₆-alkyl,hydroxyl-C₁₋₆-alkyl, R^(a)R^(b)N—C₁₋₆alkyl- and C₁₋₆-alkoxy-C₁₋₆-alkyl;and wherein if said heterocyclyl or heterocyclylcarbonyl contains a —NHmoiety that nitrogen may optionally be substituted by one or more groupsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— andC₁₋₆-alkylcarbonyl;

or R^(i) and R^(j) taken together with the nitrogen to which they areattached form a 4-9 membered heterocyclic ring, which may have anadditional heteroatom selected from the group consisting of N, O, andS(O)_(w) (wherein w is 0, 1 or 2); wherein the heterocyclic ring may beoptionally substituted on carbon by one, two, or more substituentsselected from the group consisting of halogen, hydroxyl, oxo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, R^(a)R^(b)N—, R^(a)R^(b)N—SO₂— andR^(a)R^(b)N-carbonyl-; wherein said C₁₋₆alkyl and C₁₋₆alkoxy mayoptionally be substituted the group consisting of fluorine, hydroxyl,and cyano; and wherein if said heterocyclic ring contains a —NH moietythat nitrogen may be optionally substituted by a substituent selectedfrom the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl-,C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—; whereinC₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl-, and C₁₋₆alkoxycarbonyl-may optionally be substitutedby one or more substituents selected from the group consisting offluorine, hydroxyl, and cyano;

R^(h) is independently selected for each occurrence from the groupconsisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl,C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl-,C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—; whereinC₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,C₁₋₆alkylcarbonyl-, and C₁₋₆alkoxycarbonyl-may optionally be substitutedby one or more substituents selected from R^(P);

R^(P) is independently selected, for each occurrence, from the groupconsisting of halogen, hydroxyl, cyano, C₁₋₆alkoxy, R^(i)R^(j)N—,R^(i)R^(j)N-carbonyl-, R^(i)R^(j)N—SO₂—, andR^(i)R^(j)N-carbonyl-N(R^(a))—;

R^(N) is selected from the group consisting of hydrogen, halogen,hydroxyl, and C₁₋₆alkyl; and

R^(a) and R^(b) are independently selected, for each occurrence, fromthe group consisting of hydrogen and C₁₋₄alkyl; wherein C₁₋₄alkyl mayoptionally be substituted by one or more substituents selected from thegroup consisting of halogen, cyano, oxo, and hydroxyl;

and pharmaceutically acceptable salts, stereoisomers, esters, andprodrugs thereof.

In certain embodiments, X may be N and Y may be a bond.

In certain other embodiments, X may be CR^(N) and Y may be NR^(a). Forexample, X may be CH and Y may be NH.

In certain embodiments, R¹ and R², together with the carbon or carbonsto which they are attached, may form a 4, 5, or 6-membered saturatedheterocyclic ring B having one oxygen.

In another embodiment, R¹ and R², together with the carbon or carbons towhich they are attached, may form a 4, 5, or 6-membered saturatedheterocyclic ring B having one NR^(g).

In a further embodiment, R¹ and R², together with the carbon or carbonsto which they are attached, may form a 4, 5, or 6-membered saturatedheterocyclic ring B having one S(O)₂.

In a further embodiment, R¹ and R², together with the carbon or carbonsto which they are attached, may form a 4, 5, or 6-membered saturatedcarbocyclic ring B.

In certain embodiments, a disclosed compound may represented by FormulaI.

In an embodiment, n may be 0 and m may be 1. In another embodiment, nmay be 1 and m may be 1. In a further embodiment, n may be 1 and m maybe 2.

In certain embodiments, a disclosed compound may represented by FormulaIa. For example, m may be 1.

In certain embodiments, a disclosed compound may be represented by:

In certain embodiments, A and B may be selected from the groupconsisting of:

wherein

X¹¹ is selected from the group consisting of C(R¹¹R²²), NR^(h), O, andS(O)₂; and

R¹¹ and R²² are independently selected from the group consisting ofhydrogen, halogen, —C(O)—NR^(i)R^(j),—C(O)—N(R^(a))—C₁₋₆alkylene-NR^(i)R^(j), —C₁₋₆alkylene-NR^(i)R^(j),—C₁₋₆alkylene-O—C(O)—NR^(i)R^(j), and —O—C(O)—NR^(i)R^(j).

For example, A and B may be selected from the group consisting of:

In certain embodiments, R^(h) may be selected from the group consistingof hydrogen, C₁₋₃alkyl optionally substituted by one or more fluorineatoms, —C(O)—O—C₁₋₃alkyl, —C(O)—NR^(i)R^(j), —C(O)—C₁₋₃alkyl, and—C₁₋₃alkylene-C(O)—NR^(i)R^(j). For example, R^(i) and R^(j) may beindependently selected from the group consisting of hydrogen andC₁₋₃alkyl; or R^(i) and R^(j) taken together with the nitrogen to whichthey are attached may form a 4-6 membered heterocyclic ring, which mayhave an additional heteroatom selected from the group consisting of NH,O, and S(O)_(w) (wherein w is 0, 1 or 2).

For example, R^(h) may be selected from the group consisting ofhydrogen, methyl,

In certain embodiments, R¹¹ and R²² may be hydrogen. In certain otherembodiments, R¹¹ and R²² may be fluorine atoms.

In certain embodiments, one of R¹¹ or R²² may be hydrogen and the othermay be selected from the group consisting of —C(O)—NR^(i)R^(j),—C(O)—NH—CH₂—CH₂—NR^(i)R^(j), —C(O)—NMe-CH₂—CH₂—NR^(i)R^(j),—CH₂—NR^(i)R^(j), —CH₂—O—C(O)—NR^(i)R^(j), and —O—C(O)—NR^(i)R^(j). Forexample, R^(i) and R^(j) may be independently selected from the groupconsisting of hydrogen and C₁₋₃alkyl, or R^(i) and R_(j) taken togetherwith the nitrogen to which they are attached may form a 4-6 memberedheterocyclic ring, which may have an additional heteroatom selected fromthe group consisting of N and O; wherein the heterocyclic ring may beoptionally substituted on carbon by one, two, or more fluorine atoms;and wherein if said heterocyclic ring contains a —NH moiety thatnitrogen may be optionally substituted by C₁₋₃alkyl; wherein C₁₋₃alkylmay optionally be substituted by one or more fluorine atoms.

For example, one of R¹¹ or R²² may be hydrogen and the other may beselected from the group consisting of:

Also provided herein are compounds that may be selected from the groupconsisting of:(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl3-oxa-9-azaspiro[5.5]undecane-9-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-oxa-6-azaspiro[3.3]heptane-6-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl7-oxa-2-azaspiro[3.5]nonane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-oxa-6-azaspiro[3.4]octane-6-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-oxa-7-azaspiro[3.5]nonane-7-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-oxa-2-azaspiro[3.4]octane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(7-methyl-7-azaspiro[3.5]nonan-2-yl)carbamate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(2-methyl-2-azaspiro[3.3]heptan-6-yl)carbamate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(6-methyl-6-azaspiro[3.4]octan-2-yl)carbamate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl9-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane-6-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl8-(2,2-difluoroethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxide;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl2-oxa-8-azaspiro[4.5]decane-8-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl8-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl8-oxa-2-azaspiro[4.5]decane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl9-methyl-8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(3,3-difluoroazetidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-((2-morpholinoethyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(methyl(2-morpholinoethyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6S)-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6S)-6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6S)-6-((diethylamino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;2-((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl)5-methyl(3aR,6aS)-tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(dimethylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(ethylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(methylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-isobutyrylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-propionylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(2-(diethylamino)-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(2-morpholino-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(((methylcarbamoyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(((dimethylcarbamoyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-(morpholinomethyl)-2-azaspiro[3.3]heptane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(2,2-difluoropropyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl6-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-(morpholinomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(ethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(pyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,5S,6aS)-5-((dimethylcarbamoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(1R,5S,6R)-6-(azetidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5-((diethylamino)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(3aR,6aS)-5 (((methylcarbamoyl)oxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; and a pharmaceutically acceptable salt orstereoisomer thereof.

Procedures for making compounds described herein are provided below inthe working examples and may be supplemented or substituted byprocedures known to those of skill in the art. In the reactionsdescribed below, it may be necessary to protect reactive functionalgroups (such as hydroxyl, amino, thio or carboxyl groups) to avoid theirunwanted participation in the reactions. The incorporation of suchgroups, and the methods required to introduce and remove them are knownto those skilled in the art (for example, see Greene, Wuts, ProtectiveGroups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step maybe the final step in the synthesis such that the removal of protectinggroups affords compounds of Formula I or Ia, as disclosed herein.Starting materials used in the working examples can be purchased orprepared by methods described in the chemical literature, or byadaptations thereof, using methods known by those skilled in the art.The order in which the steps are performed can vary depending on thegroups introduced and the reagents used, but would be apparent to thoseskilled in the art.

Compounds of Formula I or Ia, or any of the intermediates describedherein, can be further derivatised by using one or more standardsynthetic methods known to those skilled in the art. Such methods caninvolve substitution, oxidation or reduction reactions. These methodscan also be used to obtain or modify compounds of Formula I or Ia or anypreceding intermediates by modifying, introducing or removingappropriate functional groups. Particular substitution approachesinclude alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulfonylation, nitration, formylation,hydrolysis and coupling procedures. These procedures can be used tointroduce a functional group onto the parent molecule (such as thenitration or sulfonylation of aromatic rings) or to couple two moleculestogether (for example to couple an amine to a carboxylic acid to affordan amide; or to form a carbon-carbon bond between two heterocycles). Forexample, alcohol or phenol groups can be converted to ether groups bycoupling a phenol with an alcohol in a solvent (such as tetrahydrofuran)in the presence of a phosphine (such as triphenylphosphine) and adehydrating agent (such as diethyl, diisopropyl or dimethylazodicarboxylate). Alternatively, ether groups can be prepared bydeprotonation of an alcohol, using a suitable base (such as sodiumhydride) followed by the addition of an alkylating agent (such as analkyl halide or an alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated usinga reductive alkylation procedure. For example, the amine can be treatedwith an aldehyde and a borohydride (such as sodiumtriacetoxyborohydride, or sodium cyanoborohydride in a solvent (such asa halogenated hydrocarbon, for example dichloromethane, or an alcohol,for example ethanol) and, where necessary, in the presence of an acid(such as acetic acid).

In another example, hydroxy groups (including phenolic OH groups) can beconverted into leaving groups, such as halogen atoms or sulfonyloxygroups (such as alkylsulfonyloxy, for exampletrifluoromethanesulfonyloxy, or aryl sulfonyloxy, for examplep-toluenesulfonyloxy) using conditions known to those skilled in theart. For example, an aliphatic alcohol can be reacted with thionylchloride in a halogenated hydrocarbon (such as dichloromethane) toafford the corresponding alkyl chloride. A base (such as triethylamine)can also be used in the reaction.

In another example, ester groups can be converted to the correspondingcarboxylic acid by acid- or base-catalysed hydrolysis depending on thenature of the ester group. Acid catalysed hydrolysis can be achieved bytreatment with an organic or inorganic acid (such as trifluoroaceticacid in an aqueous solvent, or a mineral acid such as hydrochloric acidin a solvent such as dioxane). Base catalysed hydrolysis can be achievedby treatment with an alkali metal hydroxide (such as lithium hydroxidein an aqueous alcohol, for example methanol).

In another example, aromatic halogen substituents in the compounds maybe subjected to halogen-metal exchange by treatment with a base (such asa lithium base, for example n-butyl or t-butyl lithium) optionally at alow temperature (such as −78° C.) in a solvent (such as tetrahydrofuran)and the mixture may then be quenched with an electrophile to introduce adesired substituent. Thus, for example, a formyl group can be introducedby using dimethylformamide as the electrophile. Aromatic halogensubstituents can also be subjected to palladium catalysed reactions tointroduce groups such as carboxylic acids, esters, cyano or aminosubstituents.

In another example, an aryl, or heteroaryl ring substituted with anappropriate leaving group (such as a halogen or sulfonyl ester, forexample a triflate) can undergo a palladium catalysed coupling reactionwith a wide variety of substrates to form a carbon-carbon bond. Forexample, a Heck reaction can be used to couple such a ring system to analkene (which may, or may not, be further substituted) by treatment withan organopalladium complex (such astetrakis(triphenylphosphine)palladium(0), palladium (II) acetate orpalladium (II) chloride) in the presence of a ligand (such as aphosphine, for example triphenylphosphine) in the presence of a base(such as potassium carbonate or a tertiary amine, for example,triethylamine), in an appropriate solvent (such as tetrahydrofuran orDMF), under appropriate conditions (such as heating to, for example,50-120° C.). In another example, a Sonogashira reaction can be used tocouple such a ring system to an alkyne (which may, or may not be furthersubstituted) by treatment with a palladium complex (such astetrakis(triphenylphosphine)palladium(0)) and a halide salt of copper(I) (such as copper (I) iodide), in the presence of a base (such as apotassium carbonate or a tertiary amine, for example, triethylamine), inan appropriate solvent (such as tetrahydrofuran or dimethylformamide),under appropriate conditions (such as heating to, for example, 50-120°C.). In another example, a Stille reaction can be used to couple such aring system to an alkene, by treatment with an organotin compound (suchas an alkynyltin or alkenyltin reagent, for example analkenyltributylstannane) in the presence of a palladium complex (such astetrakis(triphenylphosphine)palladium(0)), with, or without the presenceof a salt (such as a copper (I) halide), in an appropriate solvent (suchas dioxane or dimethylformamide), under appropriate conditions (such asheating to, for example, 50-120° C.).

Particular oxidation approaches include dehydrogenations andaromatisation, decarboxylation and the addition of oxygen to certainfunctional groups. For example, aldehyde groups can be prepared byoxidation of the corresponding alcohol using conditions well known tothose skilled in the art. For example, an alcohol can be treated with anoxidising agent (such as Dess-Martin periodinane) in a solvent (such asa halogenated hydrocarbon, for example dichloromethane). Alternativeoxidising conditions can be used, such as treatment with oxalyl chlorideand an activating amount of dimethylsulfoxide and subsequent quenchingby the addition of an amine (such as triethylamine). Such a reaction canbe carried out in an appropriate solvent (such as a halogenatedhydrocarbon, for example dichloromethane) and under appropriateconditions (such as cooling below room temperature, for example to −78°C. followed by warming to room temperature). In another example, sulfuratoms can be oxidised to the corresponding sulfoxide or sulfone using anoxidising agent (such as a peroxy acid, for example3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenatedhydrocarbon, for example dichloromethane) at around ambient temperature.

Particular reduction approaches include the removal of oxygen atoms fromparticular functional groups or saturation (or partial saturation) ofunsaturated compounds including aromatic or heteroaromatic rings. Forexample, primary alcohols can be generated from the corresponding esteror aldehyde by reduction, using a metal hydride (such as lithiumaluminium hydride or sodium borohydride in a solvent such as methanol).Alternatively, —CH₂OH groups can be generated from the correspondingcarboxylic acid by reduction, using a metal hydride (such as lithiumaluminium hydride in a solvent such as tetrahydrofuran). In anotherexample, a nitro group may be reduced to an amine by catalytichydrogenation in the presence of a metal catalyst (such as palladium ona solid support such as carbon) in a solvent (such as an ether, forexample tetrahydrofuran, or an alcohol, such as methanol), or bychemical reduction using a metal (such as zinc, tin or iron) in thepresence of an acid (such as acetic acid or hydrochloric acid). In afurther example an amine can be obtained by reduction of a nitrile, forexample by catalytic hydrogenation in the presence of a metal catalyst(such as palladium on a solid support such as carbon), or Raney nickelin a solvent (such as tetrahydrofuran) and under suitable conditions(such as cooling to below room temperature, for example to −78° C., orheating, for example to reflux).

Salts of compounds of Formula I or Ia can be prepared by the reaction ofa compound of Formula I or Ia with an appropriate acid or base in asuitable solvent, or mixture of solvents (such as an ether, for example,diethyl ether, or an alcohol, for example ethanol, or an aqueoussolvent) using conventional procedures. Salts of compound of Formula Ior Ia can be exchanged for other salts by treatment using conventionalion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound ofFormula I or Ia, this may be produced from a corresponding mixture ofenantiomers by employing any suitable conventional procedure forresolving enantiomers. For example, diastereomeric derivatives (such assalts) can be produced by reaction of a mixture of enantiomers of acompound of Formula I or Ia (such a racemate) and an appropriate chiralcompound (such as a chiral base). The diastereomers can then beseparated by any conventional means such as crystallisation, and thedesired enantiomer recovered (such as by treatment with an acid in theinstance where the diastereomer is a salt). Alternatively, a racemicmixture of esters can be resolved by kinetic hydrolysis using a varietyof biocatalysts (for example, see Patel Steroselective Biocatalysts,Marcel Decker; New York 2000).

In another resolution process a racemate of compounds of Formula I or Iacan be separated using chiral High Performance Liquid Chromatography.Alternatively, a particular enantiomer can be obtained by using anappropriate chiral intermediate in one of the processes described above.Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the presentdisclosure.

II. Methods

Another aspect of the present disclosure provides methods of modulatingthe activity of MetAP2. Such methods comprise exposing said receptor toa compound described herein. In some embodiments, the compound utilizedby one or more of the foregoing methods is one of the generic,subgeneric, or specific compounds described herein, such as a compoundof Formula I or Ia. The ability of compounds described herein tomodulate or inhibit MetAP2 can be evaluated by procedures known in theart and/or described herein. Another aspect of the present disclosureprovides methods of treating a disease associated with expression oractivity of MetAP2 in a patient.

In certain embodiments, the present disclosure provides a method oftreating and/or controlling obesity, comprising administering to apatient in need thereof an effective amount of a disclosed compound.

In certain embodiments, the present disclosure provides a method ofinducing weight loss in a patient in need thereof, comprisingadministering to said patient an effective amount of a disclosedcompound.

In certain embodiments, the present disclosure provides a method ofsubstantially preventing weight gain in a patient in need thereof,comprising administering to said patient an effective amount of adisclosed compound.

In certain embodiments, the patient is a human.

In certain embodiments, the patient is a cat or dog.

In certain embodiments, the patient has a body mass index greater thanor equal to about 30 kg/m² before the administration.

In certain embodiments, administering a disclosed compound may comprisesubcutaneous administration. In certain embodiments, administering adisclosed compound may comprise intravenous administration.

Provided methods of treatment may include administering a disclosedcompound once, twice, or three times daily; about every other day (e.g.every 2 days); twice weekly (e.g. every 3 days, every 4 days, every 5days, every 6 days, or e.g. administered with an interval of about 2 toabout 3 days between doses); once weekly; three times weekly; everyother week; twice monthly; once a month; every other month; or even lessoften.

In certain embodiments, a method disclosed herein further comprisesadministering said compound in an amount sufficient to establishinhibition of intracellular MetAP2 effective to increase thioredoxinproduction in the patient and to induce multi organ stimulation ofanti-obesity processes in the subject.

In certain embodiments, the method comprises administering said compoundin an amount insufficient to reduce angiogenesis in the patient.

Other contemplated methods of treatment include method of treating orameliorating an obesity-related condition or co-morbidity, byadministering a compound disclosed herein to a subject. For example,contemplated herein are methods for treating type 2 diabetes in apatient in need thereof.

Exemplary co-morbidities include cardiac disorders, endocrine disorders,respiratory disorders, hepatic disorders, skeletal disorders,psychiatric disorders, metabolic disorders, and reproductive disorders.

Exemplary cardiac disorders include hypertension, dyslipidemia, ischemicheart disease, cardiomyopathy, cardiac infarction, stroke, venousthromboembolic disease and pulmonary hypertension. Exemplary endocrinedisorders include type 2 diabetes and latent autoimmune diabetes inadults. Exemplary respiratory disorders include obesity-hypoventilationsyndrome, asthma, and obstructive sleep apnea. An exemplary hepaticdisorder is nonalcoholic fatty liver disease. Exemplary skeletaldisorders include back pain and osteoarthritis of weight-bearing joints.Exemplary metabolic disorders include Prader-Willi Syndrome andpolycystic ovary syndrome. Exemplary reproductive disorders includesexual dysfunction, erectile dysfunction, infertility, obstetriccomplications, and fetal abnormalities. Exemplary psychiatric disordersinclude weight-associated depression and anxiety.

In particular, in certain embodiments, the present disclosure provides amethod of treating one of more of the above medical indicationscomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound described herein, such as a compound ofFormula I or Ia.

Obesity or reference to “overweight” refers to an excess of fat inproportion to lean body mass. Excess fat accumulation is associated withincrease in size (hypertrophy) as well as number (hyperplasia) ofadipose tissue cells. Obesity is variously measured in terms of absoluteweight, weight:height ratio, distribution of subcutaneous fat, andsocietal and esthetic norms. A common measure of body fat is Body MassIndex (BMI). The BMI refers to the ratio of body weight (expressed inkilograms) to the square of height (expressed in meters). Body massindex may be accurately calculated using either of the formulas: weight(kg)/height²(m²) (SI) or 703× weight(lb)/height²(in²) (US).

In accordance with the U.S. Centers for Disease Control and Prevention(CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and anobese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² orgreater is indicative of morbid obesity or extreme obesity. Obesity canalso refer to patients with a waist circumference of about 102 cm formales and about 88 cm for females. For children, the definitions ofoverweight and obese take into account age and gender effects on bodyfat. Patients with differing genetic background may be considered“obese” at a level differing from the general guidelines, above.

The compounds of the present disclosure also are useful for reducing therisk of secondary outcomes of obesity, such as reducing the risk of leftventricular hypertrophy. Methods for treating patients at risk ofobesity, such as those patients who are overweight, but not obese, e.g.with a BMI of between about 25 and 30 kg/m², are also contemplated. Incertain embodiments, a patient is a human.

BMI does not account for the fact that excess adipose can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat andvisceral fat, and carries higher risk of co-morbidity than “peripheralobesity”, which is typically associated with a “pear-shaped” bodyresulting from excess adiposity especially on the hips. Measurement ofwaist/hip circumference ratio (WHR) can be used as an indicator ofcentral obesity. A minimum WHR indicative of central obesity has beenvariously set, and a centrally obese adult typically has a WHR of about0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese thataccount for the ratio of excess adipose tissue to lean body mass involveobtaining a body composition of the subject. Body composition can beobtained by measuring the thickness of subcutaneous fat in multipleplaces on the body, such as the abdominal area, the subscapular region,arms, buttocks and thighs. These measurements are then used to estimatetotal body fat with a margin of error of approximately four percentagepoints. Another method is bioelectrical impedance analysis (BIA), whichuses the resistance of electrical flow through the body to estimate bodyfat. Another method is using a large tank of water to measure bodybuoyancy. Increased body fat will result in greater buoyancy, whilegreater muscle mass will result in a tendency to sink.

In another aspect, the present disclosure provides methods for treatingan overweight or obese subject involving determining a level of at leastone biomarker related to being overweight or obese in the subject, andadministering an effective amount of a disclosed compound to achieve atarget level in the subject. Exemplary biomarkers include body weight,Body Mass Index (BMI), Waist/Hip ratio WHR, plasma adipokines, and acombination of two or more thereof.

In certain embodiments, the compound utilized by one or more of theforegoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula I or Ia.

The compounds of the present disclosure may be administered to patients(animals and humans) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. It will be appreciated that thedose required for use in any particular application will vary frompatient to patient, not only with the particular compound or compositionselected, but also with the route of administration, the nature of thecondition being treated, the age and condition of the patient,concurrent medication or special diets then being followed by thepatient, and other factors which those skilled in the art willrecognize, with the appropriate dosage ultimately being at thediscretion of the attendant physician. For treating clinical conditionsand diseases noted above, a compound of this present disclosure may beadministered orally, subcutaneously, topically, parenterally, byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. Parenteral administration may include subcutaneousinjections, intravenous or intramuscular injections or infusiontechniques.

Treatment can be continued for as long or as short a period as desired.A suitable treatment period can be, for example, at least about oneweek, at least about two weeks, at least about one month, at least aboutsix months, at least about 1 year, or indefinitely. A treatment periodcan terminate when a desired result, for example a weight loss target,is achieved. A treatment regimen can include a corrective phase, duringwhich dose sufficient to provide reduction of weight is administered,and can be followed by a maintenance phase, during which a e.g. a lowerdose sufficient to prevent weight gain is administered. A suitablemaintenance dose is likely to be found in the lower parts of the doseranges provided herein, but corrective and maintenance doses can readilybe established for individual subjects by those of skill in the artwithout undue experimentation, based on the disclosure herein.Maintenance doses can be employed to maintain body weight in subjectswhose body weight has been previously controlled by other means,including diet and exercise, bariatric procedures such as bypass orbanding surgeries, or treatments employing other pharmacological agents.

III. Pharmaceutical Compositions and Kits

Another aspect of the present disclosure provides pharmaceuticalcompositions comprising compounds as disclosed herein formulatedtogether with a pharmaceutically acceptable carrier. In particular, thepresent disclosure provides pharmaceutical compositions comprisingcompounds as disclosed herein formulated together with one or morepharmaceutically acceptable carriers. These formulations include thosesuitable for oral, rectal, topical, buccal, parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous) rectal,vaginal, or aerosol administration, although the most suitable form ofadministration in any given case will depend on the degree and severityof the condition being treated and on the nature of the particularcompound being used. For example, disclosed compositions may beformulated as a unit dose, and/or may be formulated for oral orsubcutaneous administration.

Exemplary pharmaceutical compositions of this disclosure may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more disclosedcompounds, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound, or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present disclosure may alternativelybe administered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of this disclosure suitable for parenteraladministration comprise a subject composition in combination with one ormore pharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the present disclosureinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants

In another aspect, the present disclosure provides enteralpharmaceutical formulations including a disclosed compound and anenteric material; and a pharmaceutically acceptable carrier or excipientthereof. Enteric materials refer to polymers that are substantiallyinsoluble in the acidic environment of the stomach, and that arepredominantly soluble in intestinal fluids at specific pHs. The smallintestine is the part of the gastrointestinal tract (gut) between thestomach and the large intestine, and includes the duodenum, jejunum, andileum. The pH of the duodenum is about 5.5, the pH of the jejunum isabout 6.5 and the pH of the distal ileum is about 7.5. Accordingly,enteric materials are not soluble, for example, until a pH of about 5.0,of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, ofabout 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, ofabout 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, ofabout 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, ofabout 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.Exemplary enteric materials include cellulose acetate phthalate (CAP),hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetatephthalate (PVAP), hydroxypropyl methylcellulose acetate succinate(HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulosesuccinate, cellulose acetate succinate, cellulose acetatehexahydrophthalate, cellulose propionate phthalate, cellulose acetatemaleate, cellulose acetate butyrate, cellulose acetate propionate,copolymer of methylmethacrylic acid and methyl methacrylate, copolymerof methyl acrylate, methylmethacrylate and methacrylic acid, copolymerof methylvinyl ether and maleic anhydride (Gantrez E S series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro. The foregoing is a list of possible materials, but one of skillin the art with the benefit of the disclosure would recognize that it isnot comprehensive and that there are other enteric materials that wouldmeet the objectives of the present invention.

Advantageously, the present disclosure also provides kits for use bye.g. a consumer in need of weight loss. Such kits include a suitabledosage form such as those described above and instructions describingthe method of using such dosage form to mediate, reduce or preventinflammation. The instructions would direct the consumer or medicalpersonnel to administer the dosage form according to administrationmodes known to those skilled in the art. Such kits could advantageouslybe packaged and sold in single or multiple kit units. An example of sucha kit is a so-called blister pack. Blister packs are well known in thepackaging industry and are being widely used for the packaging ofpharmaceutical unit dosage forms (tablets, capsules, and the like).Blister packs generally consist of a sheet of relatively stiff materialcovered with a foil of a preferably transparent plastic material. Duringthe packaging process recesses are formed in the plastic foil. Therecesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

Also contemplated herein are methods and compositions that include asecond active agent, or administering a second active agent. Forexample, in addition to being overweight or obese, a subject or patientcan further have overweight- or obesity-related co-morbidities, i.e.,diseases and other adverse health conditions associated with,exacerbated by, or precipitated by being overweight or obese.Contemplated herein are disclosed compounds in combination with at leastone other agent that has previously been shown to treat theseoverweight- or obesity-related conditions.

For example, Type II diabetes has been associated with obesity. Certaincomplications of Type II diabetes, e.g., disability and premature death,can be prevented, ameliorated, or eliminated by sustained weight loss(Astrup, A. Pub Health Nutr (2001) 4:499-5 15). Agents administered totreat Type II diabetes include sulfonylureas (e.g., Chlorpropamide,Glipizide, Glyburide, Glimepiride); meglitinides (e.g., Repaglinide andNateglinide); biguanides (e.g., Metformin); thiazolidinediones(Rosiglitazone, Troglitazone, and Pioglitazone); dipeptidylpeptidase-4inhibitors (e.g., Sitagliptin, Vildagliptin, and Saxagliptin);glucagon-like peptide-1 mimetics (e.g., Exenatide and Liraglutide); andalpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.

Cardiac disorders and conditions, for example hypertension,dyslipidemia, ischemic heart disease, cardiomyopathy, cardiacinfarction, stroke, venous thromboembolic disease and pulmonaryhypertension, have been linked to overweight or obesity. For example,hypertension has been linked to obesity because excess adipose tissuesecretes substances that are acted on by the kidneys, resulting inhypertension. Additionally, with obesity there are generally higheramounts of insulin produced (because of the excess adipose tissue) andthis excess insulin also elevates blood pressure. A major treatmentoption of hypertension is weight loss. Agents administered to treathypertension include Chlorthalidone; Hydrochlorothiazide; Indapamide,Metolazone; loop diuretics (e.g., Bumetanide, Ethacrynic acid,Furosemide, Lasix, Torsemide); potassium-sparing agents (e.g., Amiloridehydrochloride, benzamil, Spironolactone, and Triamterene); peripheralagents (e.g., Reserpine); central alpha-agonists (e.g., Clonidinehydrochloride, Guanabenz acetate, Guanfacine hydrochloride, andMethyldopa); alpha-blockers (e.g., Doxazosin mesylate, Prazosinhydrochloride, and Terazosin hydrochloride); beta-blockers (e.g.,Acebutolol, Atenolol, Betaxolol, Bisoprolol fumarate, Carteololhydrochloride, Metoprolol tartrate, Metoprolol succinate, Nadolol,Penbutolol sulfate, Pindolol, Propranolol hydrochloride, and Timololmaleate); combined alpha- and beta-blockers (e.g., Carvedilol andLabetalol hydrochloride); direct vasodilators (e.g., Hydralazinehydrochloride and Minoxidil); calcium antagonists (e.g., Diltiazemhydrochloride and Verapamil hydrochloride); dihydropyridines (e.g.,Amlodipine besylate, Felodipine, Isradipine, Nicardipine, Nifedipine,and Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril,Enalapril maleate, Fosinopril sodium, Lisinopril, Moexipril, Quinaprilhydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers(e.g., Losartan potassium, Valsartan, and Irbesartan); Renin inhibitors(e.g., Aliskiren); and combinations thereof. These compounds areadministered in regimens and at dosages known in the art.

Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004)Vol. 89, No. 6 2601-2607) discusses a link between being overweight orobese and dyslipidemia. Dyslipidemia is typically treated with statins.Statins, HMG-CoA reductase inhibitors, slow down production ofcholesterol in a subject and/or remove cholesterol buildup fromarteries. Statins include mevastatin, lovastatin, pravastatin,simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin,dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin,rosuvastatin, pitavastatin, and glenvastatin. These compounds areadministered in regimens and at dosages known in the art. Eckel(Circulation (1997) 96:3248-3250) discusses a link between beingoverweight or obese and ischemic heart disease. Agents administered totreat ischemic heart disease include statins, nitrates (e.g., IsosorbideDinitrate and Isosorbide Mononitrate), beta-blockers, and calciumchannel antagonists. These compounds are administered in regimens and atdosages known in the art.

Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007)4:436-443) discusses a link between being overweight or obese andcardiomyopathy. Agents administered to treat cardiomyopathy includeinotropic agents (e.g., Digoxin), diuretics (e.g., Furosemide), ACEinhibitors, calcium antagonists, anti-arrhythmic agents (e.g., Sotolol,Amiodarone and Disopyramide), and beta-blockers. These compounds areadministered in regimens and at dosages known in the art. Yusef et al.(Lancet (2005) 366(9497):1640-1649) discusses a link between beingoverweight or obese and cardiac infarction. Agents administered to treatcardiac infarction include ACE inhibitors, Angiotensin II receptorblockers, direct vasodilators, beta blockers, anti-arrhythmic agents andthrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase,Anistreplase, and Urokinase). These compounds are administered inregimens and at dosages known in the art.

Suk et al. (Stroke (2003) 34:1586-1592) discusses a link between beingoverweight or obese and strokes. Agents administered to treat strokesinclude anti-platelet agents (e.g., Aspirin, Clopidogrel, Dipyridamole,and Ticlopidine), anticoagulant agents (e.g., Heparin), and thrombolyticagents. Stein et al. (The American Journal of Medicine (2005)18(9):978-980) discusses a link between being overweight or obese andvenous thromboembolic disease. Agents administered to treat venousthromboembolic disease include anti-platelet agents, anticoagulantagents, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002)58(2): 104-10) discusses a link between being overweight or obese andpulmonary hypertension. Agents administered to treat pulmonaryhypertension include inotropic agents, anticoagulant agents, diuretics,potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem),Bosentan, Epoprostenol, and Sildenafil. Respiratory disorders andconditions such as obesity-hypoventilation syndrome, asthma, andobstructive sleep apnea, have been linked to being overweight or obese.Elamin (Chest (2004) 125:1972-1974) discusses a link between beingoverweight or obese and asthma. Agents administered to treat asthmainclude bronchodilators, anti-inflammatory agents, leukotriene blockers,and anti-Ige agents. Particular asthma agents include Zafirlukast,Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone,Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex.

Kessler et al. (Eur Respir J (1996) 9:787-794) discusses a link betweenbeing overweight or obese and obstructive sleep apnea. Agentsadministered to treat sleep apnea include Modafinil and amphetamines.

Hepatic disorders and conditions, such as nonalcoholic fatty liverdisease, have been linked to being overweight or obese. Tolman et al.(Ther Clin Risk Manag (2007) 6:1153-1163) discusses a link between beingoverweight or obese and nonalcoholic fatty liver disease. Agentsadministered to treat nonalcoholic fatty liver disease includeantioxidants (e.g., Vitamins E and C), insulin sensitizers (Metformin,Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, andlipid-lowering agents.

Skeletal disorders and conditions, such as, back pain and osteoarthritisof weight-bearing joints, have been linked to being overweight or obese.van Saase (J Rheumatol (1988) 15(7):1152-1158) discusses a link betweenbeing overweight or obese and osteoarthritis of weight-bearing joints.Agents administered to treat osteoarthritis of weight-bearing jointsinclude Acetaminophen, non-steroidal anti-inflammatory agents (e.g.,Ibuprofen, Etodolac, Oxaprozin, Naproxen, Diclofenac, and Nabumetone),COX-2 inhibitors (e.g., Celecoxib), steroids, supplements (e.g.glucosamine and chondroitin sulfate), and artificial joint fluid.

Metabolic disorders and conditions, for example, Prader-Willi Syndromeand polycystic ovary syndrome, have been linked to being overweight orobese. Agents administered to treat Prader-Willi Syndrome include humangrowth hormone (HGH), somatropin, and weight loss agents (e.g.,Orlistat, Sibutramine, Methamphetamine, lonamin, Phentermine, Bupropion,Diethylpropion, Phendimetrazine, Benzphetermine, and Topamax).

Hoeger (Obstetrics and Gynecology Clinics of North America (2001)28(1):85-97) discusses a link between being overweight or obese andpolycystic ovary syndrome. Agents administered to treat polycystic ovarysyndrome include insulin-sensitizers, combinations of synthetic estrogenand progesterone, Spironolactone, Eflornithine, and Clomiphene.Reproductive disorders and conditions such as sexual dysfunction,erectile dysfunction, infertility, obstetric complications, and fetalabnormalities, have been linked to being overweight or obese. Larsen etal. (Int J Obes (Lond) (2007) 8:1189-1198) discusses a link betweenbeing overweight or obese and sexual dysfunction. Chung et al. (Eur Urol(1999) 36(1):68-70) discusses a link between being overweight or obeseand erectile dysfunction. Agents administered to treat erectiledysfunction include phosphodiesterase inhibitors (e.g., Tadalafil,Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,Alprostadil), alkaloids (e.g., Yohimbine), and testosterone. Pasquali etal. (Hum Reprod (1997) 1:82-87) discusses a link between beingoverweight or obese and infertility. Agents administered to treatinfertility include Clomiphene, Clomiphene citrate, Bromocriptine,Gonadotropin-releasing Hormone (GnRH), GnRH agonist, GnRH antagonist,Tamoxifen/nolvadex, gonadotropins, Human Chorionic Gonadotropin (HCG),Human Menopausal Gonadotropin (HmG), progesterone, recombinant folliclestimulating hormone (FSH), Urofollitropin, Heparin, Follitropin alfa,and Follitropin beta.

Weiss et al. (American Journal of Obstetrics and Gynecology (2004)190(4):1091-1097) discusses a link between being overweight or obese andobstetric complications. Agents administered to treat obstetriccomplications include Bupivacaine hydrochloride, Dinoprostone PGE2,Meperidine HCl, Ferro-folic-500/iberet-folic-500, Meperidine,Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, OxymorphoneHCl, Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide,Sufentanil citrate, and Oxytocic.

Psychiatric disorders and conditions, for example, weight-associateddepression and anxiety, have been linked to being overweight or obese.Dixson et al. (Arch Intern Med (2003) 163:2058-2065) discusses a linkbetween being overweight or obese and depression. Agents administered totreat depression include serotonin reuptake inhibitors (e.g.,Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline, andVenlafaxine); tricyclic antidepressants (e.g., Amitriptyline, Amoxapine,Clomipramine, Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine,Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline, andTrimipramine); monoamine oxidase inhibitors (e.g., Isocarboxazid,Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline,Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolidekavapyrone desmethoxyyangonin, and Dextroamphetamine); psychostimulants(e.g., Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate).

Simon et al. (Archives of General Psychiatry (2006) 63(7):824-830)discusses a link between being overweight or obese and anxiety. Agentsadministered to treat anxiety include serotonin reuptake inhibitors,mood stabilizers, benzodiazepines (e.g., Alprazolam, Clonazepam,Diazepam, and Lorazepam), tricyclic antidepressants, monoamine oxidaseinhibitors, and beta-blockers.

Another aspect of the present disclosure provides methods forfacilitating and maintaining weight loss in a subject involvingadministering to the subject an amount of a disclosed compound effectiveto result in weight loss in the subject; and optionally administering atherapeutically effective amount of a different weight loss agent tomaintain a reduced weight in the subject. Weight loss agents includeserotonin and noradrenergic re-uptake inhibitors; noradrenergicre-uptake inhibitors; selective serotonin re-uptake inhibitors; andintestinal lipase inhibitors. Particular weight loss agents includeorlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion,diethylpropion, phendimetrazine, benzphetermine, bromocriptine,lorcaserin, topiramate, or agents acting to modulate food intake byblocking ghrelin action, inhibiting diacylglycerol acyltransferase 1(DGAT1) activity, inhibiting stearoyl CoA desaturase 1 (SCD1) activity,inhibiting neuropeptide Y receptor 1 function, activating neuropeptide Yreceptor 2 or 4 function, or inhibiting activity of sodium-glucosecotransporters 1 or 2. These compounds are administered in regimens andat dosages known in the art.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein arecontemplated as compounds of the present disclosure.

Example A General Procedures

All reagents were purchased from commercial suppliers (Sigma-Aldrich,Alfa, Across etc.) and used without further purification unlessotherwise stated. THF was continuously refluxed and freshly distilledfrom sodium and benzophenone under nitrogen, and dichloromethane wascontinuously refluxed and freshly distilled from CaH₂ under nitrogen.

Reactions were monitored by TLC on silica gel 60 HSGF254 percolatedplates (0.15-0.2 mm SiO₂) and visualized using UV light (254 nm or 365nm) and/or staining with phosphomolybdic acid ethanol solution (10 g in100 mL ethanol) and subsequent heating or monitored by LCMS.

LCMS were performed on SHIMADZU LCMS-2010EV (Chromolith SpeedROD,RP-18e, 50×4.6 mm, mobile phase: Solvent A: CH₃CN/H₂O/HCOOH=10/90/0.05,Solvent B: CH₃CN/H₂O/HCOOH=90/10/0.05, 0.8 min@ 10% B, 2.7 min gradient(10-95% B), then 0.8 min@95% B, Flow rate: 3 mL/min, temperature: 40°C.).

Preparative HPLC were performed either on Method A: SHIMADZU LC-8A(Column: YMC Pack ODS-A (150*30 mm, 10 μm)) or Method B: LC-6AD (Column:Shim=Pack PREP-ODS-H (250*20 mm, 10 μm)) with UV detection which werecontrolled by LC solution Chemstation software. H₂O (0.1% HCOOH) andMeOH (MeCN) as mobile phase at the indicated flow rate.

Analytical HPLC were performed on SHIMADZU LC-2010A (ChromolithSpeedROD, RP-18e, 50×4.6 mm, mobile phase: Solvent A:CH₃CN/H₂O/HCOOH=10/90/0.05, Solvent B: CH₃CN/H₂O/HCOOH=90/10/0.05, 0.8min@ 10% B, 2.7 min gradient (10-95% B), then 0.8 min@95% B, Flow rate:3 mL/min, temperature: 40° C.).

Chiral HPLC were performed on SHIMADZU LC-2010A (Chiral column, mobilephase: Solvent A: hexane (or containing 0.1% diethylamine), Solvent B:Ethanol or Isopropanol; Flow rate: 0.8 mL/min, temperature: 30° C.).

¹H spectra were recorded on Bruker Avance II 400 MHz, Chemical shifts(δ) are reported in ppm relative to tetramethylsilane (δ=0.000 ppm), andthe spectra were calibrated to the residual solvent signal of chloroform(δ=7.26), Dimethyl sulfoxide (δ=2.50), or methanol (δ=3.30). Data for¹H-NMR spectra are reported as follows: chemical shift (multiplicity,number of hydrogens). Abbreviations are as follows: s (singlet), d(doublet), t (triplet), q (quartet), quint (quintet), m (multiple), br(broad).

Abbreviations

Ac Acetyl AcOH; HOAc acetic acid aq. Aqueous Bs Benzenesulfonyl CbzBenzyloxycarbonyl CDI Carbonyldimidazole DCM Dichloromethane DEADDiethyl azodicarboxylate DIPEA Ethyldiisopropylamine DMA Dimethylacetamide DMF Dimethyl formamide EDCI/EDC3-(ethyliminomethyleneamino)-N,N-dimethylpropan- 1-amine EtOH Ethanoleq(s). equivalent(s) EtOAc ethyl acetate Et Ethyl FA Formic acid Et₃NTriethylamine hr hour(s) HATU(Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate HOBt1-Hydroxybenzotriazole HPLC High pressure liquid chromatography LAHLithium Aluminum Hydride LCMS; LC-MS liquid chromatography massspectrometry m-CPBA m-Chloroperoxybenzoic acid MeOH Methanol mgmilligram(s) min Minute(s) mL; ml milliliter(s) NCS N-ChlorosuccinimideNMe N-methyl NMO N-methylmorpholine-N-oxide NMP N-methylpyrrolidinoneNMR Nuclear magnetic resonance Pd(dppf)Cl₂ (1,1′-bis(diphenylphosphino)ferrocene) palladium (II) dichloride PE Petroleum Ether Ph Phenyl PTSAp-Toluenesulfonic acid r.t./RT Room temperature S. Saturated SEMCl2-(Trimethylsilyl)ethoxymethyl chloride TBAF Tetrabutylammonium fluorideTEA Triethylamine THF Tetrahydrofuran THP Tetrahydropyran TFATrifluoroacetic acid TMSCN Trimethylsilyl cyanide TMSOTf TrimethylsilylTriflate THF Tetrahydrofuran TLC Thin layer chromatography Ts Tosyl(4-methylbenzene-1-sulfonyl)

PREPARATION OF INTERMEDIATES Intermediate 1(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(4-nitrophenyl) carbonate

Fumagillol (40 g, 0.142 mol) and DMAP (34.6 g, 0.283 mol) were dissolvedin anhydrous DCM (480 mL) with stirring at 0° C. A solution ofp-nitrophenyl chloroformate (48.65 g, 0.241 mol) in DCM (250 mL) wasadded drop-wise to the mixture above for 1 hr, and the temperature waskept below 0° C. After addition was complete, the mixture was stirred atroom temperature for 16 hrs. The mixture was diluted with DCM (500 mL),washed sequentially with a 10% aq. solution of citric acid, saturatedaq. K₂CO₃ and brine. The organic layer was dried, concentrated andpurified by silica gel chromatography (PE:EtOAc=20:1 toPE:EtOAc:DCM=5:1:1). The crude product was washed with PE/EtOAc (100mL/30 mL) twice, hot EtOH (200 mL, ˜70m° C.), dried under vacuum at r.t.to give(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl(4-nitrophenyl) carbonate as a white solid (47.9 g, 75.4% yield). LC-MS:m/z=448 [M+H]⁺.

¹H-NMR (400 MHz, CDCl₃) (8.39-8.23 (m, 2H), 7.53-7.34 (m, 2H), 5.63 (d,J=2.8 Hz, 1H), 5.23 (t, J=7.4 Hz, 1H), 3.74 (dd, J=11.3, 2.6 Hz, 1H),3.03 (d, J=4.2 Hz, 1H), 2.69-2.53 (m, 2H), 2.50-2.33 (m, 1H), 2.27-1.90(m, 5H), 1.77 (s, 3H), 1.68 (s, 3H), 1.37-1.06 (m, 4H).

Procedures for preparation of additional intermediates and compounds ofthe present disclosure are described in the following examples.

Intermediate 2 7-methyl-7-azaspiro[3.5]nonan-2-amine

Step 1: tert-butyl 2-(benzylamino)-7-azaspiro[3.5]nonane-7-carboxylate

To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate(1.2 g, 5.02 mmol) in methanol (20 mL) was added benzylamine (0.73 mL,6.28 mmol) and acetic acid (0.83 mL, 21.3 mmol) at 0° C. After additionwas complete, the mixture was stirred at 0° C. for 20 mins. Sodiumcyanoborohydride (327 mg, 5.02 mmol) was added in portions, and thereaction was stirred at 0° C. for 3 hrs. The reaction was quenched bythe addition of aqueous sodium hydroxide (20% wt). Then the mixture wasdiluted with water and extracted with EtOAc (30 mL×2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give a residue, which waspurified by silica gel chromatography (PE:EtOAc=3:1) to give tert-butyl2-(benzylamino)-7-azaspiro[3.5]nonane-7-carboxylate (1.2 g, 72.2% yield)as a yellow solid. LC-MS: m/z=331 [M+H]⁺.

Step 2: N-benzyl-7-methyl-7-azaspiro[3.5]nonan-2-amine

To a suspension of lithium aluminium hydride (206 mg, 5.43 mmol) in THF(7 mL) was added a solution of tert-butyl2-(benzylamino)-7-azaspiro[3.5]nonane-7-carboxylate (600 mg, 1.81 mmol)in THF (3 mL) drop-wise at 0° C. The reaction was stirred at 75° C. for45 mins. The reaction was quenched by the addition of water (0.3 mL),aqueous sodium hydroxide (0.3 mL, 15% wt) and water (0.6 mL). The solidswere removed through filtration and washed with THF. The filtrate wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive N-benzyl-7-methyl-7-azaspiro[3.5]nonan-2-amine (405 mg, 91.3%yield) as a colorless oil. LC-MS: m/z=245 [M+H]⁺.

Step 3: 7-methyl-7-azaspiro[3.5]nonan-2-amine

A solution of N-benzyl-7-methyl-7-azaspiro[3.5]nonan-2-amine (350 mg,1.43 mmol) in methanol (10 mL) was degassed under N₂ atmosphere threetimes, and Pd(OH)₂ on carbon (130 mg) was added. The mixture wasdegassed with N₂ again and stirred under a H₂ atmosphere at roomtemperature overnight. The mixture was filtered through Celite, and thefiltrate was concentrated to give 7-methyl-7-azaspiro[3.5]nonan-2-amine(190 mg, 85.5% yield) as a colorless oil. LC-MS: m/z=155 [M+H]⁺.

Intermediate 3 7-methyl-2,7-diazaspiro[3.5]nonan, trifluoroacetate

Step 1: tert-butyl 3-(2-morpholinoethyl)azetidine-1-carboxylate

To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (600mg, 2.65 mmol) in DCE (10 mL) was added an aqueous solution offormaldehyde (37 percent w/w, 238 mg, 3.98 mmol). After the reaction wasstirred at room temperature for 10 min, sodium triacetoxyborohydride(1.69 g, 7.95 mmol) was added and the mixture was stirred for another 3hrs. After the solvent was removed, the residue was dissolved in EtOAcand washed with brine. The EtOAc layer was dried and concentrated togive a residue, which was purified by silica gel chromatography(DCM:MeOH=100:1 to 10:1) to give tert-butyl3-(2-morpholinoethyl)azetidine-1-carboxylate (410 mg, 64.35% yield) as awhite solid. LC-MS: m/z=185 [M+H]⁺

Step 2: 7-methyl-2,7-diazaspiro[3.5]nonan, trifluoroacetate

To a solution of tert-butyl 3-(2-morpholinoethyl)azetidine-1-carboxylate(400 mg, 1.66 mmol) in DCM (5 mL) was added TFA (2.5 mL) drop-wise at 0°C. The reaction was stirred room temperature for 1 hr. The mixture wasconcentrated under reduced pressure to give7-methyl-2,7-diazaspiro[3.5]nonane trifluoroacetate (390 mg, 96.1%yield) as a yellow syrup, which was directly used to the next reactionwithout purification. LC-MS: m/z=141 [M+H]⁺.

Intermediate 4 7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonanetrifluoroacetate

Step 1: tert-butyl7-(2,2-difluoroacetyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a solution of 2,2-difluoroacetic acid (424.3 mg, 4.42 mmol) in DCM(10 mL) was added HOBt (358.0 mg, 2.65 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (635.0 mg,3.31 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 30min, and DIPEA (1.14 g, 12.04 mmol) was added drop-wise. Then tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (500.0 mg, 2.21 mmol) was addeddrop-wise at 0° C. The reaction was then stirred at room temperature for2 hrs. The mixture was then concentrated to dryness while keeping thetemperature below 30° C. The residue was suspended in ice-water, and theslurry was stirred for 10 min. The mixture was then filtered, and thefilter cake was washed with water, followed by cold EtOH. The filtercake was then dried under vacuum to give a crude product, which wasrecrystallized with ethanol to give tert-butyl7-(2,2-difluoroacetyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (560 mg,83.3% yield) as a white solid. LC-MS: m/z 305 [M+H]⁺.

Step 2: tert-butyl7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a solution of tert-butyl7-(2,2-difluoroacetyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (560 mg,1.84 mmol) in THF (anhydrous, 50 mL) was added a solution ofborane-tetrahydrofuran complex (6.0 mL, 6.0 mmol, 1M in THF) dropwise at−10° C. over 10 min. The reaction was stirred at room temperatureovernight. To the reaction mixture was then added MeOH (20 mL) dropwiseat 0° C. After the mixture was stirred at room temperature for 30 min itwas concentrated under vacuum. The residue was dissolved in EtOH/water(9 mL/1 mL) and stirred at reflux overnight. The mixture wasconcentrated under vacuum to give a residue, which was purified bysilica gel column chromatography (DCM:methanol=100:1 to 40:1) to givetert-butyl 7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate(470 mg, 89.0% yield) as a colorless oil. LC-MS: m/z 291 [M+H-56]⁺.

Step 3: 7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate

To a mixture of tert-butyl7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (470 mg,1.62 mmol) in DCM (5 mL) was added TFA (2.0 mL) drop-wise at 0° C. Thereaction was stirred at room temperature for 1 hr. The mixture wasconcentrated under reduced pressure to give7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (400mg, 95.1% yield) as a yellow syrup, which was directly used to next stepwithout purification. LC-MS: m/z 191 [M+H]⁺.

Intermediate 5 2-methyl-2-azaspiro[3.3]heptan-6-amine

Step 1: 2-methyl-2-azaspiro[3.3]heptan-6-amine

To a solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate(500 mg, 2.35 mmol) in THF (anhydrous, 5 mL) was added lithium aluminiumhydride (268.8 mg, 7.07 mmol) in portions at 0° C. The mixture washeated to 65° C. overnight. The mixture was quenched by aqueous sodiumhydroxide solution (0.3 mL, 15% wt) and water (0.3 mL). The slurry wasfiltered and the filter cake was washed with dichloromethane twice, thecombined filtrates was dried over anhydrous Na₂SO₄ and concentrated togive (R)-(1-methylpyrrolidin-2-yl)methanol (290.2 mg, 97.6% yield) as ayellow oil. LC-MS: m/z 127 [M+H]⁺.

Intermediate 6 6-methyl-6-azaspiro[3.4]octan-2-amine

Step 1: tert-butyl2-((methylsulfonyl)oxy)-6-azaspiro[3.4]octane-6-carboxylate

To a solution of tert-butyl2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate (1 g, 4.41 mmol) indichloromethane (10 mL) was added triethylamine (1.22 mL, 8.82 mmol)followed by methanesulfonyl chloride (0.5 mL, 6.62 mmol) drop-wise at 0°C. The reaction was stirred at room temperature overnight. The mixturewas diluted with dichloromethane and washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (petroleum ether:ethyl acetate=3:1) to givethe titled compound (1.3 g, 97.1% yield) as a colorless oil. LC-MS: m/z250 [M+H-56]⁺.

Step 2: tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate

To a solution of tert-butyl2-((methylsulfonyl)oxy)-6-azaspiro[3.4]octane-6-carboxylate (1.3 g, 4.24mmol) in DMF (15 mL) was added sodium azide (414 mg, 6.37 mmol) inportions at 0° C. The mixture was stirred at 80° C. overnight. Themixture was diluted with diethyl ether and washed with brine, dried overNa₂SO₄ and concentrated to give 1-(azidomethyl)-4-methoxybenzene (1.02g, 93.4% yield) as a yellow oil, which was used in next step withoutfurther purification.

Step 3: tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate

A solution of tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate (1g, 3.96 mmol) in MeOH (20 mL) was degassed under N₂ atmosphere for threetimes, then Pd/C (100 mg, 10% wt) was added in one portion. The mixturewas stirred under H₂ atmosphere at room temperature overnight. Themixture was filtered through a pad of celite and the filtrate wasconcentrated under vacuum to give tert-butyl2-amino-6-azaspiro[3.4]octane-6-carboxylate (420 mg, 46.7% yield) as acolorless oil. LC-MS: m/z 227 [M+H]⁺.

Step 4: 6-methyl-6-azaspiro[3.4]octan-2-amine

To a solution of tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate(420 mg, 1.85 mmol) in THF (anhydrous, 10 mL) was added lithiumaluminium hydride (211 mg, 5.57 mmol) in portions at 0° C. The mixturewas heated to 65° C. overnight. The mixture was quenched by aqueoussodium hydroxide solution (0.3 mL, 15% wt) and water (0.3 mL). Theslurry was filtered and the filter cake was washed with dichloromethanetwice, the combined filtrates was dried over anhydrous Na₂SO₄ andconcentrated to give 6-methyl-6-azaspiro[3.4]octan-2-amine (250 mg,96.1% yield) as a colorless oil. LC-MS: m/z 141 [M+H]⁺.

Intermediate 7 2-methyl-2,6-diazaspiro[3.3]heptanes oxalate

Step 1: (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol

To a mixture of 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (3.0 g, 11.84 mmol)in Et₂O (30 mL) was added aq. HBr (4.50 mL, 33.16 mmol, 40%) dropwise at0° C. The reaction was warmed to room temperature and stirred for 1 hr.The mixture was diluted with ethyl acetate and washed with water, brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (petroleum ether:ethyl acetate=5:1 to 1:1) togive (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (3.4 g, 84.8% yield)as a white solid. LC-MS: m/z=336 [M+H]⁺.

Step 2: 3,3-bis(bromomethyl)-1-tosylazetidine

To a mixture of (3-(bromomethyl)-1-tosylazetidin-3-yl)methanol (3.3 g,9.87 mmol) and CBr₄ (5.57 g, 16.78 mmol) in dichloromethane (50 mL) wasadded PPh₃ (4.40 g, 16.78 mmol) at 0° C. under N₂. The reaction wasstirred at room temperature overnight. The mixture was diluted withdichloromethane, washed with water, brine, dried over anhydrous Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=50:1 to 3:1) to give3,3-bis(bromomethyl)-1-tosylazetidine (2.1 g, 53.5% yield) as a yellowsolid. LC-MS: m/z=397 [M+H]⁺.

Step 3: 2-benzyl-6-tosyl-2,6-diazaspiro[3.3]heptane

To a mixture of 3,3-bis(bromomethyl)-1-tosylazetidine (1.6 g, 4.03 mmol)in acetonitrile (20 mL) was added benzylamine (1.10 mL, 10.07 mmol) andDIPEA (4.16 mL, 24.17 mmol) drop-wise. The reaction was stirred atreflux overnight. The mixture was concentrated and the residue wasdissolved in dichloromethane. The dichloromethane solution was washedwith water, brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography (petroleum ether:ethylacetate=5:1 to 2:1) to give 2-benzyl-6-tosyl-2,6-diazaspiro[3.3]heptane(1.2 g, 87.0% yield) as a yellow solid. LC-MS: m/z=343 [M+H]⁺.

Step 4: 2-tosyl-2,6-diazaspiro[3.3]heptane

To a solution of 2-benzyl-6-tosyl-2,6-diazaspiro[3.3]heptane (1.2 g,3.50 mmol) in degassed methanol (20 mL) was added Pd/C (120 mg, 10% wt)under N₂ atmosphere. The mixture was degassed again and stirred under aH₂ atmosphere for 1.5 hrs. The mixture was filtered through Celite, andthe filtrate was concentrated under reduced pressure to give2-tosyl-2,6-diazaspiro[3.3]heptane (880 mg, 99.5% yield) as a whitesolid. LC-MS: m/z=253 [M+H]⁺.

Step 5: 2-methyl-6-tosyl-2,6-diazaspiro[3.3]heptane

To a solution of 2-tosyl-2,6-diazaspiro[3.3]heptane (850 g, 3.37 mmol)in methanol (20 mL) was added aqueous HCHO (5.57 mL, 20.21 mmol)followed by sodium cyanoborohydride (2.54 g, 40.42 mmol) in portions at0° C. The reaction was stirred at room temperature for 1 hr. Thereaction mixture was then quenched with saturated aqueous sodiumbicarbonate and diluted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel column chromatography (dichloromethane:methanol=100:0 to30:1) to give 2-methyl-6-tosyl-2,6-diazaspiro[3.3]heptane (620 mg, 69.1%yield) as a yellow solid. LC-MS: m/z=267 [M+H]⁺.

Step 6: 2-methyl-2,6-diazaspiro[3.3]heptanes oxalate

To a solution of 2-methyl-6-tosyl-2,6-diazaspiro[3.3]heptane (600 mg,2.25 mmol) in methanol (30 mL) was added Mg (432.5 mg, 18.02 mmol). Thereaction was sonicated for 2 hrs and stirred at reflux overnight. Thereaction mixture was concentrated and Na₂SO₄-10H₂O (6.0 g) and ethanol(5 mL) were added. After the mixture was stirred at room temperature for1 hr, it was filtered and the filtrate was dried over Na₂SO₄ andconcentrated. To the residue was added oxalic acid (101.4 mg, 1.13 mmol)and ethanol (1 mL). The reaction mixture was stirred at room temperatureand a yellow precipitate was formed. The solid was filtered and dried togive 2-methyl-2,6-diazaspiro[3.3]heptane oxalic acid salt (300 mg, 65.8%yield) as a yellow solid. LC-MS: m/z=113 [M+H]⁺.

Intermediate 8 (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole

Step 1: (3R,4S)-dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate

To a solution of 2-(benzylamino)acetic acid (5 g, 30.3 mmol) in toluene(30 ml) was added dimethyl maleate (2.90 g, 20.3 mmol), paraformaldehyde(5.45 g, 60.6 mmol) and DIPEA (3.5 ml, 30.3 mmol). The reaction wasstirred at reflux overnight. The reaction mixture was diluted with EtOAcand washed with water and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give aresidue, which was purified by silica gel column chromatography(petroleum ether:EtOAc=1:1) to give (3R,4S)-dimethyl1-benzylpyrrolidine-3,4-dicarboxylate (3 g, 35.8% yield) as a yellowoil. LC-MS: m/z 278 [M+H]⁺.

Step 2: ((3R,4S)-1-benzylpyrrolidine-3,4-diyl)dimethanol

To a slurry of lithium aluminium hydride (1.0 g, 26.3 mmol) in THF(anhydrous, 15 mL) was added a solution of (3R,4S)-dimethyl1-benzylpyrrolidine-3,4-dicarboxylate (2.43 g, 8.7 mmol) in THF(anhydrous, 15 mL) dropwise at 0° C. over 30 min. The reaction wasstirred at room temperature overnight. The reaction was quenched withwater (1 mL), aqueous NaOH solution (1 mL, 15% wt) and water (3 mL)successively. The slurry was filtered and the cake was washed with EtOActwice. The combined filtrate was dried with anhydrous Na₂SO₄ andconcentrated to give ((3R,4S)-1-benzylpyrrolidine-3,4-diyl)dimethanol(1.8 g, 94.7% yield) as a yellow oil. LC-MS: m/z 222 [M+H]⁺.

Step 3: (3aR,6aS)-5-benzylhexahydro-1H-furo[3,4-c]pyrrole

To a solution of ((3R,4S)-1-benzylpyrrolidine-3,4-diyl)dimethanol (1.3g, 5.9 mmol) in toluene (15 ml) was added p-toluenesulfonic acid (1.3 g,7.0 mmol). The resulting mixture was heated under a Dean Stark trap at120° C. for 20 hrs. The reaction mixture was diluted with EtOAc andwashed with water and brine. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give a residue, whichwas purified by silica gel column chromatography (petroleum ether:ethylacetate=5:1) to give (3aR,6aS)-5-benzylhexahydro-1H-furo[3,4-c]pyrrole(800 mg, 67.2% yield) as a yellow oil. LC-MS: m/z 204 [M+H]⁺.

Step 4: (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole

A solution of (3aR,6aS)-5-benzylhexahydro-1H-furo[3,4-c]pyrrole (500 mg,2.46 mmol) in ethanol (10 mL) was degassed with N₂ for three times andPd(OH)₂/C (60 mg, 10% wt) was added. The mixture was degassed again andstirred under H₂ atmosphere at room temperature for 16 hrs. The mixturewas filtered and the filtrate was concentrated under reduced pressure togive (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (270 mg, 96.7% yield) asa yellow oil. LC-MS: m/z 114 [M+H]⁺.

Intermediate 9 3-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane

Step 1: 3-benzyl-3,9-diazaspiro[5.5]undecane

To a suspension of LiAlH₄ (314 mg, 8.26 mmol) in anhydrous THF (1 mL)was added 9-benzyl-3,9-diazaspiro[5.5]undecane-2,4-dione (750 mg, 2.75mmol) in portions at −10° C. under a N₂ atmosphere. The resultingmixture was stirred at 70° C. overnight. The reaction was quenched byaddition of NaSO₄.10H₂O at 0° C. Ater stirred for 30 min, the mixturewas filtered and the filtrate was concentrated under reduced pressure.The residue was diluted with EtAOc and washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give3-benzyl-3,9-diazaspiro[5.5]undecane (600 mg, 89.2% yield) as a yellowoil, which was directly used to next step without purification. LC-MSm/z: 245 [M+H]⁺.

Step 2:1-(9-benzyl-3,9-diazaspiro[5.5]undecan-3-yl)-2,2-difluoroethanone

To a solution of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)aceticacid (600 mg, 2.46 mmol) in DCM (25 mL) was sequentially added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (458 mg,2.95 mmol) and 1-hydroxybenzotriazole (380 mg, 2.95 mmol), and thenDIPEA (1.70 mL, 9.82 mmol) was added drop-wise. The mixture was stirredfor 10 min and 2,2-difluoroacetic acid (283 mg, 2.95 mmol) was added.The reaction was stirred at room temperature overnight. The reaction wasdiluted with DCM (50 mL×2) and washed with water (50 mL), brine (50 mL),dried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (DCM:MeOH=100:1 to 50:1 to give1-(9-benzyl-3,9-diazaspiro[5.5]undecan-3-yl)-2,2-difluoroethanone (750mg, 94.8% yield) as a colorless oil. LC-MS m/z: 323 [M+H-56]⁺.

Step 3: 3-benzyl-9-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane

To a solution of1-(9-benzyl-3,9-diazaspiro[5.5]undecan-3-yl)-2,2-difluoroethanone (750mg, 2.33 mmol) in THF (anhydrous, 20 mL) was added a solution ofborane-tetrahydrofuran complex (9.31 mL, 9.31 mmol, 1M in THF) dropwiseat −10° C. over 30 min. The reaction was stirred at room temperatureovernight. After the reaction mixture was cooled to 0° C., MeOH (10 mL)was added drop-wise, and resulting mixture was stirred at roomtemperature for 30 min. The mixture was then concentrated under vacuumto give a yellow reside, which was dissolved in EtOH/H₂O (9 mL/1 mL) andstirred at reflux overnight. The resulting mixture was concentratedunder vacuum. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=5:1) to give3-benzyl-9-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane (400 mg,55.8% yield) as a colorless oil. LC-MS m/z: 309 [M+H]⁺.

Step 4: 3-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane

A solution of 3-benzyl-9-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane(400 mg, 1.3 mmol) in MeOH (10 mL) was degassed three times under N₂atmosphere, Pd(OH)₂ (40 mg, 10% wt) and a drop of acetic acid was added.The mixture was degassed again and stirred under H₂ atmosphere at roomtemperature overnight. The reaction was filtered through Celite, and thefiltrate was concentrated to give3-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane (300 mg, crude) as acolorless oil. LC-MS m/z: 219 [M+H]⁺.

Intermediate 10 2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane

Step 1: tert-butyl6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate

To a solution of tert-butyl7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (2.3 g, 10.16 mmol) in DMF(15 mL) was added NaH (813.2 mg, 20.33 mmol, 60% dispersion in mineraloil) in portions at 0° C. After the mixture was stirred at 0° C. for 30min, benzylbromide (1.45 mL, 12.20 mmol) was added dropwise. Thereaction was then stirred at room temperature overnight. The reactionwas quenched with ice water and extracted with EtOAc (50 mL×2). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (petroleum ether:EtOAc=5:1 to 1:2) to give tert-butyl6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (2.9 g, 90.1%yield) as a colorless oil. LC-MS m/z: 317 [M+H]⁺.

Step 2: 6-benzyl-2,6-diazaspiro[3.4]octan-7-one

To a mixture of tert-butyl6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (900 mg, 2.84mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL) dropwise at 0°C. The reaction was stirred at room temperature for 1 hr. The mixturewas concentrated under reduced pressure to give6-benzyl-2,6-diazaspiro[3.4]octan-7-one trifluoroacetate (610 mg, 99.1%yield) as a yellow syrup, which was directly used to the next reactionwithout purification. LC-MS m/z: 217 [M+H]⁺.

Step 3: 6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octan-7-one

To a solution of 6-benzyl-2,6-diazaspiro[3.4]octan-7-one (900.0 mg, 4.16mmol) in acetonitrile (10 mL) was added DIPEA (1.21 mL, 7.01 mmol) and2,2-difluoroethyl trifluoromethanesulfonate (500 mg, 2.34 mmol). Thereaction was stirred at room temperature overnight. The mixture was thenconcentrated and the residue was dissolved in EtOAc (50 mL). Thesolution was washed with water (50 mL×2), dried and concentrated. Theresidue was purified by silica gel column chromatography (DCM:MeOH=100:1to 50:1) to give6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octan-7-one (600 mg,91.7% yield) as a brown oil. LC-MS m/z: 281 [M+H]⁺.

Step 4: 6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane

To a solution of6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octan-7-one (600 mg,2.14 mmol) in dry THF (10 mL) was added a solution ofborane-tetrahydrofuran complex (8.56 mL, 8.56 mmol, 1M in THF) dropwiseat −10° C. over 10 min. The reaction was stirred at room temperatureovernight. The reaction mixture was cooled to 0° C., MeOH (10 mL) wasadded dropwise, and resulting mixture was stirred at room temperaturefor 30 min. The mixture was then concentrated and the residue wasdissolved in EtOH/water (9 mL/1 mL) and stirred at reflux overnight. Theresulting mixture was concentrated under vacuum and the residue waspurified by silica gel column chromatography (DCM:MeOH=100:0 to 30:1) togive 6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane (450 mg,78.9% yield) as a colorless oil. LC-MS m/z: 267 [M+H]⁺.

Step 5: 2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane

To a solution of6-benzyl-2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane (450 mg, 1.69mmol) in MeOH (10 mL) was added three drops of acetic acid and Pd/C (45mg, 10% wt). The resulting mixture was degassed and stirred under a H₂atmosphere at room temperature for 5 hrs. The mixture was filteredthrough a pad of Celite. The filtrate was concentrated under reducedpressure to give 2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane (290mg, 97.3% yield) as a colorless oil. LC-MS m/z: 177 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 10 by using appropriate startingmaterials.

Intermediate # Structure LC-MS 11

205 [M + H]+ 12

177 [M + H]⁺

Intermediate 13

Step 1: tert-butyl6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate(400 mg, 2.02 mmol) in MeCN (5 mL) was added DIPEA (782 mg, 6.06 mmol)and 2,2-difluoroethyl trifluoromethanesulfonate (563 mg, 2.63 mmol) at0° C. The resulting mixture was stirred at room temperature overnight.The mixture was concentrated, and the residue was partitioned betweenDCM (20 mL) and water (10 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (DCM:MeOH=50:1 to 20:1) to give tert-butyl6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (230 mg,43.9% yield) as a colourless oil. LC-MS m/z: 263 [M+H]⁺.

Step 2: 2-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptanetrifluoroacetate

To a solution of tert-butyl6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg1.14 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0° C. Thereaction was then stirred at room temperature for 2 hrs. The resultingmixture was concentrated under vacuum to give a residue, which wasco-evaporated with toluene (1 mL×2) to give2-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane trifluoroacetate (400mg, 100% yield) as a brown oil, which was directly used to the nextreaction without purification. LC-MS m/z: 163 [M+H]⁺.

Intermediate 14(1R,5S,6r)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

Step 1: ethyl5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate

To a solution of 1-benzyl-1H-pyrrole-2,5-dione (15.0 g, 80.13 mmol) intoluene (80 mL) was added ethyl 2-diazoacetate (10.16 g, 80.13 mmol, 90%solution in DCM). The resulting mixture was stirred at 100° C. for 5hrs. The mixture was concentrated under vacuum to give a yellow reside,which was diluted with EtOAc (100 mL), washed with brine (30 mL×2). Thecombined aqueous layers were back-extracted with EtOAc (30 mL×2). Thecombined organic layers was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (petroleumether:ethyl acetate=100:1˜20:1) to give the titled compound (15.2 g,62.96% yield) as a white solid. LC-MS m/z: 302 [M+H]⁺.

Step 2: (1R,5S,6r)-ethyl3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate

Ethyl5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate(8 g, 22.56 mmol) was slowly added to a flask which was heated to 190°C. The melted mixture was stirred at this temperature for 1 hour. Themixture was cooled to room temperature and diluted with ether. Thesolution was cooled in a dry ice acetone bath for about 2 hours. Theprecipitated solid was collected by filtration and washed small volumeof ether to afford the titled compound (4.1 g, 56.5% yield) as a whitesolid. LC-MS m/z: 302 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ 7.28-7.19 (m,5H), 4.44 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 2.80 (d, J=2.8 Hz, 2H), 2.20(t, J=2.8 Hz, 1H), 1.17 (dt, J=7.0, 4.8 Hz, 3H).

Step 3: (1R,5S,6r)-ethyl3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate

To a solution of (1R,5S,6r)-ethyl3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (4.0 g, 14.64mmol) in THF (50 mL) was added BH₃-Me₂S (2N solution in THF 30 mL, 60mmol) dropwise at 0° C. over a period of 30 minutes. The resultingmixture was stirred at reflux for 6 hours. The reaction was cooled 0°C., quenched by adding aqueous NH₄Cl solution and, extracted with EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=50:1˜10:1) to afford(1R,5S,6r)-ethyl 3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.1g, 58.5% yield) as a white solid. LC-MS m/z: 246 [M+H]⁺.

Step 4: (1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

To a stirred solution of (1R,5S,6r)-ethyl3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (2 g, 2.95 mmol) in1,4-dioxane (10 mL) was added NaOH solution (10 mL, 2 N) in portions at0° C. The reaction was stirred at room temperature for 16 hrs. The pHwas adjusted to around 5 by progressively addition of aqueous 1N HClsolution. The mixture was then concentrated under vacuum to give(1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.6 g,90.33% yield) as a white solid. LC-MS m/z: 218 [M+H]⁺.

Step 5:(1R,5S,6r)-3-benzyl-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a stirred solution of(1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (600 mg,2.76 mmol) in DCM (10 mL) were sequentially added EDCI (794 mg, 4.14mmol), HOBt (559 mg, 4.14 mmol), methylamine hydrochloride (373 mg, 5.52mmol) and DIPEA (1.90 mL, 11.05 mmol). The reaction mixture was stirredat room temperature for 12 hrs, and then diluted with water andextracted with EtOAc. The organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel column chromatography (petroleum ether:ethylacetate=10:1˜1:1) to give(1R,5S,6r)-3-benzyl-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide(320 mg, 50.3% yield) as a yellow oil. LC-MS m/z: 231 [M+H]⁺.

Step 6: (1R,5S,6r)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of(1R,5S,6r)-3-benzyl-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide(320 mg, 1.39 mmol) in MeOH (10 mL) was added Pd(OH)₂ (390.26 mg, 0.139mmol, 5% weight). The reaction mixture was stirred under hydrogenatmosphere at 45° C. for 2 hrs. The reaction mixture was filteredthrough a short pad of Celite and the filtrate was concentrated toafford (1R,5S,6r)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (190mg, 97.5% yield) as a yellow oil. LC-MS m/z: 141 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 14 by using corresponding amines asstarting materials.

Intermediate # Structure LC-MS 15

155 [M + H]+ 16

127 [M + H]⁺ 17

203 [M + H]⁺ 18

183 [M + H]⁺ 19

240 [M + H]⁺ 20

254 [M + H]⁺

Intermediate 21(1R,5S,6r)-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane

Step 1:((1R,5S,6r)-3-benzyl-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane

To a solution of((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)(3,3-difluoroazetidin-1-yl)methanone(610 mg, 2.0 mmol) in dry THF (10 mL) was added a solution of BH₃-THF (6mL, 5.0 mmol, 1 M in THF) dropwise at −10° C. The resulting mixture wasstirred at r.t. overnight. After it was cooled to 0-5° C., MeOH wasadded dropwise below 10° C., and the resulting mixture was stirred atr.t for 30 min. The mixture was concentrated under vacuum, and theresidue was dissolved in EtOH/H₂O (8 mL/1 mL) and stirred at refluxovernight. The resulting mixture was concentrated under vacuum and theresidue was purified by silica gel column chromatography (DCM:MeOH=150:0to 50:1) to give((1R,5S,6r)-3-benzyl-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane(420 mg, 73.1% yield) as a colorless oil. LC-MS m/z: 279 [M+H]⁺.

Step 2:(1R,5S,6r)-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane

To a stirred solution of((1R,5S,6r)-3-benzyl-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane(300 mg, 1.1 mmol) in MeOH (10 mL) was added Pd(OH)₂ on carbon (50 mg,10% wt). The reaction mixture was degassed and stirred under a H₂atmosphere at 45° C. for 2 hrs. The reaction mixture was cooled and andfiltered through a small pad of Celite. The filtrate was concentratedunder reduced pressure to give(1R,5S,6r)-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane(210 mg, 98.6% yield) as a yellow solid. LC-MS m/z: 189 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 21 by using appropriate startingmaterial.

Intermediate # Structure LC-MS 22

183 [M + H]⁺ 23

169 [M + H]⁺

Intermediate 24 (3aR,6aS)-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Step 1: (3aR,6aS)-methyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (500mg, 2.5 mmol) in dry DCM (8 mL) was added TEA (0.9 mL, 7.5 mmol) andmethyl chloroformate (310 mg, 2.75 mmol) at 0° C. After the resultingmixture was stirred at room temperature overnight, it was partitionedbetween buffer (pH 4.0, 20 mL) and DCM. The organic layer was dried overanhydrous Na₂SO₄, and concentrated. The residue was purified by silicagel column chromatography (DCM:MeOH=200:1) to give (3aR,6aS)-methyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (210 mg, 32.3%yield) as a colorless oil. LC-MS m/z: 261 [M+H]⁺.

Step 2: (3aR,6aS)-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (210 mg, crude) in MeOH(5 mL) was added Pd(OH)₂ on carbon (50 mg, 10% wt) and a drop of HOAc.The mixture was degassed and stirred under a H₂ atmosphere at 45° C.overnight. The reaction mixture was filtered through a pad of Celite,and the filtrate was concentrated to give (3aR,6aS)-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (180 mg, 100% yield) asa light brown oil. LC-MS m/z: 171 [M+H]⁺.

Intermediate 25(3aR,6aS)—N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

Step 1:(3aR,6aS)-5-benzyl-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a mixture of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (500mg, 2.47 mmol) in dry DCM (5 mL) was added DMAP (30 mg, 0.24 mmol), TEA(623 mg, 6.17 mmol) and dimethylcarbamic chloride (317 mg, 2.96 mmol) at0° C. The resulting mixture was stirred at room temperature overnightand concentrated. The residue was partitioned between EtOAc (20 mL) andwater (10 mL). The organic layer was washed with water, dried overanhydrous Na₂SO₄, and concentrated. The residue was purified by silicagel column chromatography (DCM:MeOH=50:1) to give(3aR,6aS)-5-benzyl-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(660 mg, 97.9% yield) as a colourless oil. LC-MS m/z: 274 [M+H]⁺.

Step 2:(3aR,6aS)—N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a solution of(3aR,6aS)-5-benzyl-N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(500 mg 1.83 mmol) in MeOH (5 mL) was added a drop of AcOH and Pd(OH)₂on carbon (50 mg, 10% wt) at 0° C. The reaction was degassed and stirredunder a H₂ atmosphere at 45° C. overnight. The reaction mixture wascooled and filtered through a pad of Celite. The filtrate wasconcentrated to give(3aR,6aS)—N,N-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(380 mg, 100% yield) as a colourless oil, which was directly used to thenext reaction without purification. LC-MS m/z: 184 [M+H]⁺.

Intermediate 26(3aR,6aS)—N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

Step 1:(3aR,6aS)-5-benzyl-N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a solution of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (500mg, 2.47 mmol) in DCM (5 mL) was added TEA (275 mg, 2.72 mmol) and ethylisocyanate (184 mg, 2.59 mmol) at 0° C. The resulting mixture wasstirred at room temperature overnight. The mixture was concentrated, andthe residue was partitioned between EtOAc (20 mL) and water (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography (DCM:MeOH=50:1)to give(3aR,6aS)-5-benzyl-N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(430 mg, 63.8% yield) as a colourless oil. LC-MS m/z: 274 [M+H]⁺.

Step 2:(3aR,6aS)—N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a solution of(3aR,6aS)-5-benzyl-N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(430 mg 1.57 mmol) in MeOH (5 mL) was added a drop of AcOH and Pd(OH)₂/C(43 mg, 10% wt) at 0° C. The reaction mixture was degassed and stirredunder a H₂ atmosphere at 45° C. overnight. The resulting mixture wascooled and filtered through a pad of Celite. The filtrate wasconcentrated to give(3aR,6aS)—N-ethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (280mg, 100% yield) as a colourless oil, which was directly used to the nextreaction without purification. LC-MS m/z: 184 [M+H]⁺.

Intermediate 27(3aR,6aS)—N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

Step 1:(3aR,6aS)-5-benzyl-N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a solution of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (500mg, 2.47 mmol) in anhydrous DCM (5 mL) was added DIPEA (637 mg, 4.94mmol) and 2,5-dioxopyrrolidin-1-yl methylcarbamate (850 mg, 494 mmol) at0° C. The resulting mixture was stirred at room temperature overnight.The mixture was concentrated, and residue was partitioned between EtOAc(20 mL) and water (10 mL). The organic layer was washed with water (10mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography (DCM:MeOH=50:1) to give(3aR,6aS)-5-benzyl-N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(300 mg, 46.9% yield) as a colourless oil. LC-MS m/z: 260 [M+H]⁺.

Step 2:(3aR,6aS)—N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

To a solution of(3aR,6aS)-5-benzyl-N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide(300 mg 1.16 mmol) in MeOH (5 mL) was added a drop of AcOH and Pd(OH)₂on carbon (30 mg, 10% wt) at 0° C. The reaction was degassed and stirredunder a H₂ atmosphere at 45° C. overnight. The resulting mixture wascooled and filtered through a pad of Celite. The filtrate wasconcentrated in vacuo to give(3aR,6aS)—N-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (200mg, 100% yield) as a colourless oil, which was directly used to the nextreaction without purification. LC-MS m/z: 160 [M+H]⁺.

Intermediate 28

Step1:1-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylpropan-1-one

To a solution of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (500mg, 2.47 mmol) in anhydrous DCM (20 mL) was added TEA (0.86 mL, 6.18mmol) and DMAP (50 mg) at 0° C. The mixture was stirred at 0° C. for 10min and isobutyryl chloride (0.3 mL, 0.97 mmol) were added. Afteraddition, the mixture was stirred at room temperature overnight. Thereaction mixture was diluted with NH₄OAc buffer (pH 4.0, 20 mL) andextracted with DCM (20 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bysilica gel column chromatography (DCM:MeOH=100:1) to give1-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylpropan-1-one(450 mg, 66.8% yield) as a colorless oil. LC-MS m/z: 273 [M+H]⁺.

Step2:1-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylpropan-1-one

To a solution of1-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylpropan-1-one(450 mg, 1.65 mmol) in MeOH (10 mL) was added Pd(OH)₂ on carbon (50 mg,10% wt) and a drop of HOAc. The mixture was degassed and stirred under aH₂ atmosphere at 45° C. overnight. The reaction was filtered through apad of Celite, and the filtrate was concentrated to give1-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-methylpropan-1-one(250 mg, 83.0% yield) as a light brown oil. LC-MS m/z: 183 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 28 by using appropriate startingmaterial.

Intermediate # Structure LC-MS 29

169 [M + H]⁺

Intermediate 30N,N-diethyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetamide

Step 1: (3aR,6aS)-methyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-2-benzyloctahydropyrrolo[3,4-c]pyrrole (1.2g, 6.0 mmol) in acetonitrile (10 mL) was added DIPEA (3.1 mL, 18.0 mmol)and tert-butyl 2-bromoacetate (1.8 g 9.0 mmol) at 0° C. After addition,the mixture was stirred at room temperature overnight. The reactionmixture was concentrated and the residue was partitioned between DCM (50mL) and water (15 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography (DCM:MeOH=50:1 to give (3aR,6aS)-methyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.15 g, 57.1%yield) as a colorless oil. LC-MS m/z: 371 [M+H]⁺.

Step 2: tert-butyl2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetic acidtrifluoroacetate

To a solution of (3aR,6aS)-methyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.15 g, 3.1mmol) in DCM (8 mL) was added TFA (2 mL) dropwise at 0° C. The reactionwas then stirred at rt overnight. The reaction mixture was concentratedto give2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetic acidtrifluoroacetate (2.7 g, 100% yield) as a yellow oil. LC-MS m/z: 261[M+H]⁺.

Step 3:2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N,N-diethylacetamide

To a solution of2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetic acid(1.3 g, 1.5 mmol) in DCM (10 mL) was added EDCI (520 mg 2.7 mmol) andHOBt (300 mg 2.2 mmol), diethylamine (401 mg, 5.4 mmol) and DIPEA (2.1mL, 11.2 mmol). The resulting mixture was stirred at room temperaturefor 12 hrs, and then diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM:MeOH=50:1) to give2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N,N-diethylacetamide(420 mg, 88.7% yield) as a yellow oil. LC-MS m/z: 316 [M+H]⁺.

Step 4:N,N-diethyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetamide

To a solution of2-((3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N,N-diethylacetamide(420 mg, 1.33 mmol) in MeOH (5 mL) was added Pd(OH)₂ on carbon (50 mg,10% wt.) and a drop of HOAc. The mixture was degassed and stirred undera H₂ atmosphere at 45° C. overnight. The reaction was filtered through apad of Celite, and the filtrate was concentrated to giveN,N-diethyl-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetamide(280 mg, 93.3% yield) as a brown oil. LC-MS m/z: 226 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 30 by using appropriate startingmaterial.

Intermediate # Structure LC-MS 31

240 [M + H]⁺

Intermediate 32 (1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethylmethylcarbamate

Step 1: ((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol

To a solution of (1R,5S,6r)-methyl3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (1 g, 3.66mmol) in dry THF (10 mL) was added LiAlH₄ (695 mg, 18.3 mmol) inportions at 0° C., and the reaction was stirred to 50° C. overnight. Themixture was cooled and carefully quenched with water (0.7 mL), aqueousNaOH solution (0.7 mL, 15% wt) followed by water (2.1 mL). The slurrywas filtered, and the filter cake was washed with EtOAc. The filtratewas extracted with EtOAc (20 mL×2) and the combined organic layers weredried over anhydrous Na₂SO₄ and concentrated to give((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol (750 mg,96.1% yield) as a yellow oil. LC-MS m/z: 204 [M+H]⁺.

Step 2: ((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl4-nitrophenyl carbonate

To a solution of((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol (800 mg,3.94 mmol) and DMAP (961 mg, 7.88 mmol) in anhydrous DCM (10 mL) wasadded a solution of p-nitrophenyl chloroformate (1.34 g, 6.69 mmol) inDCM (5 mL) dropwise over 30 min at 0° C. After addition, the mixture wasstirred at room temperature for 16 hrs. The mixture was diluted with DCM(10 mL), washed sequentially with 10% aqueous citric acid solution,saturated aqueous K₂CO₃ solution and brine. The organic layer was driedover anhydrous Na₂SO₄ and concentrated and the residue was purified bysilica gel column chromatography (DCM:MeOH=80:1) to give the titledproduct (800 mg, 55.1% yield) as a yellow oil. LC-MS m/z: 368 [M+H]⁺.

Step 3: ((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methylmethylcarbamate

To a mixture methylamine hydrochloride (200 mg, 3.0 mmol) in MeCN (20mL) and DIPEA (1 mL, 6 mmol) was added((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl 4-nitrophenylcarbonate (800 mg, 2.17 mmol) in portions at 0° C. After the reactionwas stirred at rt overnight, the mixture was concentrated. The residuewas dissolved in DCM (20 mL) and washed with ammonium acetate buffer(pH-4, 15 mL x 2). The organic layer was washed with aq. NaHCO₃ solution(15 mL x 2, 5% wt), dried over Na₂SO₄ and concentrated. The residue waspurified via silica gel column chromatography (petroleum ether:ethylacetate=3:1) to give the titled product (300 mg, 53.1% yield) as acolorless oil. LC-MS m/z: 261[M+H]⁺.

Step 4: (1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl methylcarbamate

To a solution of((1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methyldimethylcarbamate (300 mg, 1.15 mmol) in MeOH (6 mL) was added Pd(OH)₂(45 mg, 10% wt) and a drop of HOAc. The mixture was degassed and stirredunder a H₂ atmosphere at 45° C. for 2 hrs. The reaction was filteredthrough a pad of Celite, and the filtrate was concentrated to give(1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl methylcarbamate (190 mg,96.6% yield) as a light yellow oil. LC-MS m/z: 171 [M+H]⁺.

The following intermediate was prepared according to procedures similarto that described for Intermediate 32 by using appropriate startingmaterial.

Intermediate # Structure LC-MS 33

185 [M + H]⁺

Intermediate 34 4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholinetrifluoroacetate

Step 1: (3,3-dimethoxycyclobutane-1,1-diyl)dimethanol

To a suspension of LiAlH₄ (7.16 g, 188.65 mmol) in dry THF (70 mL) wasadded a solution of diisopropyl3,3-dimethoxycyclobutane-1,1-dicarboxylate (17.0 g, 58.95 mmol) in THF(80 mL) dropwise at 0° C. The mixture was stirred at room temperatureovernight. The reaction was quenched by addition of water (7.16 mL),aqueous sodium hydroxide solution (7.16 mL, 15% wt) and water (21.48mL). The mixture was stirred at room temperature for 15 min andfiltered. The filter cake was then washed with EtOAc (100 mL×2). Thecombined filtrates were dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel column chromatography (petroleumether:EtOAc=5:1 to 1:3) to give(3,3-dimethoxycyclobutane-1,1-diyl)dimethanol (7.3 g, 70.2% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 3.79 (m, 2H), 3.68 (m, 2H), 3.50(s, 6H), 3.15 (s, 1H), 2.89 (s, 1H), 2.10 (m, 2H), 1.91 (m, 2H).

Step 2: (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene)dimethanesulfonate

To a solution of (3,3-dimethoxycyclobutane-1,1-diyl)dimethanol (7.3 g,41.43 mmol) in DCM (70 mL) was added TEA (34.55 mL, 248.57 mmol) andmethanesulfonyl chloride (9.62 mL, 124.28 mmol) dropwise at 0° C. Thereaction was stirred at room temperature for 2 hrs. The mixture wasdiluted with DCM and washed with water. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (petroleum ether:EtOAc=10:1 to 1:1) to give(3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene) dimethanesulfonate(11.9 g, 86.4% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.22(s, 4H), 3.08 (s, 6H), 2.98 (s, 6H), 2.04 (s, 4H).

Step 3: 6,6-dimethoxy-2-tosyl-2-azaspiro[3.3]heptane

To a solution of (3,3-dimethoxycyclobutane-1,1-diyl)bis(methylene)dimethanesulfonate (5 g, 15.04 mmol) in DMSO (50 mL) was added solidK₂CO₃ (10.40 g, 75.21 mmol) and 4-methylbenzenesulfonamide(2.83 g, 16.55mmol). The reaction was then stirred at at 85° C. overnight. The mixturewas diluted with EtOAc (100 mL), washed with water. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column chromatography (petroleum ether:EtOAc=10:1to 2:1) to give 6,6-dimethoxy-2-tosyl-2-azaspiro[3.3]heptane (4.2 g,89.6% yield) as a white solid. LC-MS m/z: 312 [M+H]⁺.

Step 4: 2-tosyl-2-azaspiro[3.3]heptan-6-one

To a mixture of 6,6-dimethoxy-2-tosyl-2-azaspiro[3.3]heptane (4.0 g,12.85 mmol) in aqueous HCl solution (60 mL, 3M) was stirred at roomtemperature overnight. The mixture was concentrated to give2-tosyl-2-azaspiro[3.3]heptan-6-one (3.1 g, 90.9% yield) as a whitesolid. LC-MS m/z: 266 [M+H]⁺.

Step 5: 6-(methoxymethylene)-2-tosyl-2-azaspiro[3.3]heptane

To a solution of (methoxymethyl)triphenylphosphonium (3.88 g, 11.31mmol) in dry THF (40 mL) was added LiHMDS (9.05 mL, 9.05 mmol) at −10°C. The resulting mixture was stirred at this temperature for 1 hr. Thena solution of 2-tosyl-2-azaspiro[3.3]heptan-6-one (2.0 g, 7.54 mmol) inTHF (anhydrous, 20 mL) was added dropwise. The reaction was stirred atroom temperature for 4 hrs. The mixture was then cooled to 0° C.,quenched with water, extracted with EtOAc (50 mL) The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography (petroleum ether:EtOAc=10:1 to 2:1) to give6-(methoxymethylene)-2-tosyl-2-azaspiro[3.3]heptane (950 mg, 42.9%yield) as a white solid. LC-MS m/z: 296 [M+H]⁺.

Step 6: 2-tosyl-2-azaspiro[3.3]heptane-6-carbaldehyde

To a solution of 6-(methoxymethylene)-2-tosyl-2-azaspiro[3.3]heptane(920 mg, 3.14 mmol) in THF (10 mL) was added aqueous HCl(10 mL, 1M). Thereaction was stirred at room temperature for 4 hrs. The mixture wasdiluted with DCM (50 mL), washed with water (50 mL). The organic layerwas dried over Na₂SO₄ and concentrated to give2-tosyl-2-azaspiro[3.3]heptane-6-carbaldehyde (850 mg, 97.0% yield) as awhite solid. LC-MS m/z: 280 [M+H]⁺.

Step 7: (2-tosyl-2-azaspiro[3.3]heptan-6-yl)methanol

To a solution of 2-tosyl-2-azaspiro[3.3]heptane-6-carbaldehyde (850 mg,3.04 mmol) in EtOH (10 mL) was added NaBH₄ (115.1 mg, 3.04 mmol) inportions at 0° C. The mixture was then stirred at room temperature for 2hrs. The reaction was quenched with aqueous 1M HCl at 0° C., and themixture was extracted with DCM (50 mL×2). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column chromatography (petroleum ether:EtOAc=2:1to 1:2) to give (2-tosyl-2-azaspiro[3.3]heptan-6-yl)methanol (850 mg,99.2% yield) as a yellow solid. LC-MS m/z: 282 [M+H]⁺.

Step 8: (2-tosyl-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate

To a solution of (2-tosyl-2-azaspiro[3.3]heptan-6-yl)methanol (850 mg,3.02 mmol) in DCM (10 mL) was added TEA (1.26 mL, 9.06 mmol) andmethanesulfonyl chloride (0.35 mL, 4.53 mmol) dropwise at 0° C. Thereaction was stirred at room temperature for 3 hrs. The mixture wasdiluted with DCM and washed with water. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (petroleum ether:EtOAc=3:1 to 1:1) to give(2-tosyl-2-azaspiro[3.3]heptan-6-yl)methyl methanesulfonate (1.0 g,92.0% yield) as a white solid. LC-MS m/z: 360 [M+H]⁺.

Step 9: 4-((2-tosyl-2-azaspiro[3.3]heptan-6-yl)methyl)morpholine

To a solution of (2-tosyl-2-azaspiro[3.3]heptan-6-yl)methylmethanesulfonate (500 mg, 1.39 mmol) in acetonitrile (20 mL) was addedmorpholine (0.24 mL, 2.78 mmol), DIPEA (0.48 mL, 2.78 mmol) and NaI (50mg, 0.33 mmol). The reaction was stirred at reflux overnight. Themixture was then concentrated and the residue was partitioned betweenEtOAc (50 mL) and water (50 mL). The organic layer was washed withwater, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by silica gel column chromatography (DCM:MeOH=100:1 to 50:1) togive 4-((2-tosyl-2-azaspiro[3.3]heptan-6-yl)methyl)morpholine (450 mg,92.3% yield) as a brown solid. LC-MS m/z: 351 [M+H]⁺.

Step 10: 4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholine

To a solution of4-((2-tosyl-2-azaspiro[3.3]heptan-6-yl)methyl)morpholine (420 mg, 1.20mmol) in MeOH (5 mL) was added Na amalgam (2.1 g, 5% wt). The reactionwas stirred at reflux overnight. The solution was decanted from theliquid Hg, and the residue was washed with methanol. The solutions wereconcentrated to give 4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholine (210mg, 89.2% yield) as a gray solid, which was directly used to the nextreaction without purification. LC-MS m/z: 197 [M+H]⁺.

Step 11: tert-butyl6-(morpholinomethyl)-2-azaspiro[3.3]heptane-2-carboxylate

A solution of 4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholine (210 mg,1.07 mmol) in H₂O (5 mL) was adjusted to pH 10 with aqueous NaOHsolution (2 M) at 0° C. The solution was diluted with acetone (5 mL) and(Boc)₂O (218.3 mg, 1.28 mmol) was added. After the mixture was stirredat room temperature overnight, it was extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography (DCM:MeOH=100:1to 30:1) to give tert-butyl6-(morpholinomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (270 mg, 85.1%yield) as a yellow solid. LC-MS m/z: 297 [M+H]⁺.

Step 12: 4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholine

To a mixture of tert-butyl6-(morpholinomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (270 mg, 0.91mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at 0° C. The reactionwas stirred at room temperature for 2 hrs. The mixture was concentratedunder reduced pressure to give4-(2-azaspiro[3.3]heptan-6-ylmethyl)morpholine trifluoroacetate (170 mg,95.0% yield) as a yellow syrup, which was directly used to the nextreaction without purification. LC-MS m/z: 197 [M+H]⁺.

Example 1 General Procedure for Coupling of Intermediates

A general procedure for preparation of compounds of the presentdisclosure is provided below using Example 1 as an illustration.

To a mixture of an appropriate intermediate compound in CH₃CN was addedDIPEA drop-wise at 0-5° C. The mixture was then stirred at 0-5° C. for10 min, and carbonate Intermediate 1 was added to the mixture inportions at 0° C. under a N₂ atmosphere. The reaction mixture wasstirred at 25° C. until the reaction was complete as judged by TLC. Thesolvent was removed under vacuum below 40° C. The residue was dilutedwith DCM, and the DCM diluent was washed with ammonium acetate buffer(pH-4). The combined aqueous layers were back-extracted with DCM. Thecombined organic layers were washed with aq. NaHCO₃ solution, dried overNa₂SO₄ and concentrated. Purification by silica gel columnchromatography (DCM:MeOH=100:0 to 60:1), followed by preparative HPLC(Method A, H₂O (0.1% FA)/CH₃CN) gave the title compound.Characterization data are provided below.

The following compounds were prepared according to procedures similar tothat described for Example 1 by using the corresponding intermediates.

Example Intermediate Structure LC-MS H-NMR (400 MHz, CDCl₃) 1Commercially available material

464 [M + H]⁺ 5.48-5.50 (m, 1H), 5.11-5.16 (m, 1H), 3.54-3.60 (m, 5H),3.34-3.37 (m, 7H), 2.92-2.93 (d, J = 4.0 Hz, 1H), 2.47-2.51 (m, 2H),2.26-2.33 (m, 1H), 2.05-2.13 (m, 1H), 1.87- 2.00 (m, 2H), 1.72-1.94 (m,2H), 1.67 (s, 3H), 1.58 (s, 3H), 1.44 (s, 8H), 1.14 (s, 3H), 1.00-1.05(m, 1H) 2 Commercially available material

408 [M + H]⁺ 5.45 (d, J = 3.2 Hz, 1H), 5.19- 5.06 (m, 1H), 4.73-4.68 (m,4H), 4.10-4.02 (m, 4H), 3.54 (m, 1H), 3.36 (s, 3H), 2.92 (d, J = 4.3 Hz,1H), 2.51-2.47 (m, 2H), 2.36-2.22 (m, 1H), 2.13-2.06 (m, 1H), 2.02- 1.94(m, 1H), 1.87-1.71 (m, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.13 (s, 3H),1.04-0.95 (m, 1H) 3 Commercially available material

436 [M + H]⁺ 5.45 (m, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.53-3.64 (m, 8H),3.39 (s, 3H), 2.92 (d, J = 4.3 Hz, 1H), 2.46- 2.52 (m, 2H), 2.28-2.29(m, 1H), 1.95-2.11 (m, 2H), 1.78-1.86 (m, 2H), 1.67-1.77 (m, 6H), 1.59(s, 3H), 1.52 (s, 3H), 1.14 (s, 3H), 0.91- 1.01 (m, 1H) 4 Commerciallyavailable material

422 [M + H]⁺ 5.59 (d, J = 3.2 Hz, 1H), 5.22-5.24 (m, 1H), 4.68-4.70 (m,1H), 4.56- 4.63 (m, 3H), 3.57-3.69 (m, 3H), 3.33-3.52 (m, 2H), 3.47 (s,3H), 2.99-3.03 (dd, J = 11.2, 4.4 Hz, 1H), 2.55-2.63 (m, 2H), 2.35-2.40(m, 1H), 2.15-2.21 (m, 3H), 2.07-2.11 (m, 1H), 1.86-1.98 (m, 3H), 1.76(s, 3H), 1.67-1.68 (d, J = 4 Hz, 3H), 1.22-1.32 (d, J = 4 Hz, 3H), 1.07-1.13 (m, 1H) 5 Commercially available material

435 [M + H]⁺ 5.48 (d, J = 2.7 Hz, 1H), 5.14 (m, 1H), 4.43-4.31 (m, 4H),3.56 (m, 1H), 3.37 (s, 3H), 3.31 (s, 4H), 2.92 (d, J = 4.3 Hz, 1H),2.54-2.44 (m, 2H), 2.30 (m, 1H), 2.09 (m, 1H), 2.01-1.87 (m, 2H),1.83-1.73 (m, 5H), 1.68 (s, 3H), 1.59 (s, 3H), 1.18 (s, 1H), 1.14 (s,3H), 1.06-0.99 (m, 1H) 6 Commercially available material

422 [M + H]⁺ 5.46 (d, J = 3.3 Hz, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.87(t, J = 15.7 Hz, 4H), 3.78 (dd, J = 9.8, 6.4 Hz, 4H), 3.54 (dt, J =10.8, 5.4 Hz, 1H), 3.43- 3.36 (m, 3H), 2.91 (d, J = 4.3 Hz, 1H), 2.48(dd, J = 10.1, 5.3 Hz, 2H), 2.37-2.24 (m, 1H), 2.13- 2.03 (m, 3H), 1.96(dd, J = 13.6, 4.5 Hz, 1H), 1.89-1.83 (m, 1H), 1.78 (dd, J = 12.4, 6.0Hz, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H), 1.03-0.96(m, 1H) 7  2

463 [M + H]⁺ 5.39 (s, 1H), 5.10-5.15 (m, 1H), 4.84 (d, J = 7.6 Hz, 1H),4.02-4.06 (m, 1H), 3.54-3.57 (m, 1H), 3.38 (s, 3H), 2.90 (d, J = 4.4 Hz,1H), 2.47- 2.48 (m, 6H), 206-2.33 (m, 5H), 1.91-1.99 (m, 2H), 1.71-1.85(m, 6H), 1.62-1.67 (m, 7H), 1.58 (s, 3H), 1.13 (s, 3H), 0.93-1.00 (m,1H) 8  3

449 [M + H]⁺ 5.54 (d, J = 3.0 Hz, 1H), 5.29 - 5.15 (m, 1H), 3.78 (d, J =48.8 Hz, 4H), 3.64 (dd, J = 11.2, 2.7 Hz, 1H), 3.45 (d, J = 9.9 Hz, 3H),2.90 (dd, J = 79.5, 21.1 Hz, 4H), 2.57 (q, J = 4.0 Hz, 5H), 2.43-2.31(m, 1H), 2.18 (dt, J = 14.8, 7.3 Hz, 1H), 2.11-2.00 (m, 5H), 1.99-1.92(m, 1H), 1.90-1.82 (m, 2H), 1.76 (s, 2H), 1.68 (s, 3H), 1.22 (s, 3H),1.12- 1.02 (m, 1H) 9  4

499 [M + H]⁺ 5.82 (tt, J = 55.8, 4.3 Hz, 1H), 5.45 (d, J = 3.2 Hz, 1H),5.18-5.09 (m, 1H), 3.71-3.50 (m, 5H), 3.38 (s, 3H), 2.91 (d, J = 4.3 Hz,1H), 2.66 (td, J = 15.0, 4.3 Hz, 2H), 2.48 (dt, J = 10.2, 6.1 Hz, 6H),2.29 (dt, J = 13.7, 6.6 Hz, 1H), 2.10 (dt, J = 14.8, 7.4 Hz, 1H), 1.98(td, J = 13.5, 4.4 Hz, 1H), 1.92-1.83 (m, 1H), 1.82-1.69 (m, 6H), 1.68(s, 3H), 1.59 (s, 3H), 1.14 (s, 3H), 1.03- 0.94 (m, 1H) 10  5

435 [M + H]⁺ 5.38 (s, 1H), 5.13 (t, J = 8.0 Hz, 1H), 4.98 (d, J = 6.8Hz, 1H), 3.86- 3.93 (m, 5H), 3.53-3.57 (m, 1H), 3.35 (s, 3H), 2.90 (d, J= 4.4 Hz, 1H), 2.56-2.62 (m, 5H), 2.27-2.31 (m, 1H), 2.08-2.13 (m, 3H),1.73- 1.92 (m, 4H), 1.76 (s, 3H), 1.67 (s, 3H), 1.18 (s, 3H), 0.98 (d, J= 8.8 Hz, 1H) 11  6

449 [M + H]⁺ 5.47 (s, 1H), 5.05-5.23 (m, 2H), 4.13-4.16 (m, 1H), 3.44(s, 3H), 3.11-3.32 (m, 4H), 2.97 (d, J = 4.4 Hz, 1H), 2.72 (s, 3H),2.55-2.59 (m, 2H), 2.33-2.47 (m, 3H), 1.90-2.22 (m, 9H), 1.76 (s, 3H),1.67 (s, 3H), 1.21 (s, 3H), 1.05 (d, J = 8.8 Hz, 1H) 12  7

421 [M + H]⁺ 5.44 (d, J = 3.2 Hz, 1H), 5.19-5.09 (m, 1H), 3.94 (m, 4H),3.53 (m, 1H), 3.37 (s, 3H), 3.26 (m, 4H), 2.91 (m, 1H), 2.51-2.44 (m,2H), 2.34-2.24 (m, 1H), 2.23 (s, 3H), 2.10 (m, 1H), 2.02-1.93 (m, 1H),1.89-1.70 (m, 5H), 1.68 (s, 3H), 1.13 (s, 3H), 1.03-0.95 (m, 1H) 13  8

422 [M + H]⁺ 5.49 (s, 1H), 5.18-5.08 (m, 1H), 3.83 (dt, J = 16.8, 8.4Hz, 2H), 3.71- 3.42 (m, 5H), 3.37 (d, J = 13.4 Hz, 3H), 3.32-3.10 (m,2H), 2.90 (t, J = 13.2 Hz, 3H), 2.49 (dd, J = 13.2, 5.4 Hz, 2H),2.34-2.21 (m, 1H), 2.10 (dt, J = 17.8, 7.3 Hz, 1H), 2.04-1.85 (m, 2H),1.84-1.72 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.16 (d, J = 17.3 Hz,3H), 1.02 (d, J = 12.6 Hz, 1H) 14  9

527 [M + H]⁺ 5.90 (t, J = 55.4 Hz, 1H), 5.48 (d, J = 3.1 Hz, 1H),5.20-5.09 (m, 1H), 3.56 (dd, J = 11.1, 2.7 Hz, 1H), 3.37 (s, 3H),3.36-3.29 (m, 3H), 2.92 (d, J = 4.3 Hz, 1H), 2.72 (t, J = 13.2 Hz, 2H),2.62-2.43 (m, 6H), 2.34-2.24 (m, 1H), 2.09 (dt, J = 14.7, 7.3 Hz, 1H),2.01-1.88 (m, 2H), 1.78 (dd, J = 12.4, 5.1 Hz, 2H), 1.68 (s, 3H), 1.59(s, 3H), 1.52 (s, 4H), 1.38 (d, J = 29.3 Hz, 4H), 1.13 (d, J = 6.7 Hz,3H), 1.02 (dd, J = 11.1, 3.8 Hz, 1H) 15 10

485 [M + H]⁺ 5.68 (m, 1H), 5.49 (s, 1H), 5.13 (m, 1H), 3.59-3.18 (m,12H), 2.92 (m, 1H), 2.74 (m, 2H), 2.56-2.44 (m, 2H), 2.29 (m, 1H),2.16-2.05 (m, 1H), 2.04-1.88 (m, 3H), 1.85 (m, 1H), 1.77 (m, 2H), 1.68(s, 3H), 1.59 (d, J = 4.5 Hz, 3H), 1.14 (d, J = 2.5 Hz, 3H), 1.01 (d, J= 13.6 Hz, 1H) 16 11

513 [M + H]⁺ 5.87 (m, 1H), 5.57 (s, 1H), 5.19 (d, J = 20.0 Hz, 1H), 3.62(m, 1H), 3.54-3.30 (m, 5H), 3.27 (d, J = 10.8 Hz, 1H), 3.15 (m, 1H),3.03- 2.95 (m, 1H), 2.79-2.67 (m, 2H), 2.66-2.31 (m, 7H), 2.22-2.02 (m,2H), 1.99-1.79 (m, 3H), 1.74 (s, 3H), 1.71 (m, 2H), 1.66 (s, 3H), 1.60(m, 4H), 1.21 (s, 3H), 1.09 (m, 1H) 17 12

485 [M + H]⁺ 5.84 (s, 1H), 5.45 (s, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.85(s, 4H), 3.54 (dd, J = 11.2, 2.7 Hz, 1H), 3.38 (s, 3H), 2.91 (d, J = 4.3Hz, 1H), 2.89- 2.56 (m, 5H), 2.48 (dd, J = 14.8, 5.2 Hz, 2H), 2.29 (dt,J = 13.5, 6.6 Hz, 1H), 2.16-1.91 (m, 4H), 1.90- 1.81 (m, 1H), 1.78 (dd,J = 10.2, 6.0 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.18 (s, 1H), 1.12(d, J = 6.2 Hz, 3H), 0.99 (dd, J = 10.5, 3.4 Hz, 1H) 18 13

471 [M + H]⁺ 5.67 (tt, J = 55.8, 4.3 Hz, 1H), 5.43 (s, 1H), 5.18-5.10(m, 1H), 3.95 (m, 4H), 3.53 (dd, J = 11.2, 2.7 Hz, 1H), 3.40 (d, J = 3.4Hz, 3H), 3.37 (s, 3H), 2.91 (d, J = 4.3 Hz, 1H), 2.70 (m, 2H), 2.52-2.45(m, 2H), 2.35-2.23 (m, 1H), 2.09 (dt, J = 14.8, 7.3 Hz, 1H), 1.97 (dt, J= 13.5, 4.2 Hz, 1H), 1.88-1.71 (m, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.12(s, 3H), 1.02-0.96 (m, 1H) 19 Commercially available material

485 [M + H]⁺ 6.08 (t, J = 55.6 Hz, 1H), 5.35 (s, 1H), 5.20 (t, J = 7.5Hz, 1H), 3.54 (dd, J = 11.1, 2.4 Hz, 3H), 3.29 (s, 3H), 3.14 (d, J = 9.1Hz, 2H), 2.86 (d, J = 4.4 Hz, 1H), 2.80 (dd, J = 15.8, 11.8 Hz, 4H),2.63 (t, J = 7.8 Hz, 2H), 2.58 (d, J = 4.4 Hz, 1H), 2.56-2.51 (m, 3H),2.18 (t, J = 6.8 Hz, 2H), 2.08 (s, 1H), 1.97 (td, J = 13.3, 4.4 Hz, 1H),1.78 (dd, J = 16.4, 11.6 Hz, 2H), 1.71 (s, 3H), 1.62 (s, 3H), 1.08 (s,3H), 1.01 (d, J = 13.4 Hz, 1H) 20 Commercially available material

435 [M + H]⁺ 5.34 (s, 1H), 5.18-5.21 (m, 1H), 3.49-3.55 (m, 4H), 3.28(s, 3H), 3.09-3.17 (m, 3H), 2.86 (d, J = 4.0 Hz, 1H), 2.79 (s, 2H),2.54-2.58 (m, 2H), 2.51 (s, 3H), 2.25 (s, 3H), 2.16-2.19 (m, 2H),1.94-2.00 (m, 1H), 1.76-1.81 (m, 2H), 1.71 (s, 3H), 1.61 (s, 3H), 1.08(s, 3H), 1.01 (d, J = 13.6 Hz, 1H) 21 Commercially available material

362 [M + H]⁺ 5.52 (d, J = 10.7 Hz, 1H), 5.22 (t, J = 7.5 Hz, 1H),3.66-3.53 (m, 2H), 3.53-3.24 (m, 6H), 2.99 (d, J = 4.3 Hz, 1H),2.64-2.47 (m, 2H), 2.37- 2.33 (m, 1H), 2.20-2.13 (m, 1H), 2.09-2.00 (m,1H), 1.99-1.79 (m, 3H), 1.75 (s, 3H), 1.66 (s, 3H), 1.54-1.39 (m, 2H),1.20 (s, 3H), 1.07 (d, J = 13.6 Hz, 1H), 0.69 (d, J = 7.2 Hz, 1H),0.26-0.14 (m, 1H) 22 Commercially available material

428 [M + H]⁺ 7.54 (d, J = 23.9 Hz, 1H), 6.78 (d, J = 14.7 Hz, 1H), 5.74(d, J = 9.2 Hz, 1H), 5.45 (s, 1H), 5.12 (t, J = 7.1 Hz, 1H), 4.44-4.33(m, 1H), 4.11- 3.99 (m, 1H), 3.91 (dd, J = 13.8, 6.0 Hz, 1H), 3.54 (dd,J = 11.3, 2.4 Hz, 1H), 3.36 (d, J = 21.0 Hz, 4H), 3.11 (s, 1H), 2.90(td, J = 20.1, 9.6 Hz, 4H), 2.65 (s, 3H), 2.54-2.45 (m, 2H), 2.28 (dd, J= 14.2, 6.5 Hz, 1H), 2.19-2.03 (m, 4H), 1.96- 1.83 (m, 2H), 1.78 (s,1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.18 (s, 1H), 1.11 (s, 3H), 1.00 (d, J= 7.6 Hz, 1H), 0.84 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H) 23Commercially available material

456 [M + H]⁺ 5.57 (d, J = 2.9 Hz, 1H), 5.23 (t, J = 7.5 Hz, 1H),4.44-4.13 (m, 8H), 3.64 (dd, J = 11.3, 2.7 Hz, 1H), 3.52-3.39 (m, 3H),3.01 (d, J = 4.3 Hz, 1H), 2.61-2.53 (m, 2H), 2.44- 2.33 (m, 1H), 2.18(dt, J = 14.8, 7.3 Hz, 1H), 2.05 (td, J = 13.3, 5.0 Hz, 1H), 1.97-1.86(m, 2H), 1.83 (d, J = 11.3 Hz, 1H), 1.78 (d, J = 8.4 Hz, 3H), 1.68 (s,3H), 1.21 (s, 3H), 1.14-1.06 (m, 1H) 24 Commercially available material

450 [M + H]⁺ 5.49 (s, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.80 (t, J = 7.1Hz, 2H), 3.57 (dd, J = 11.1, 2.7 Hz, 1H), 3.49 (s, 2H), 3.44-3.16 (m,6H), 2.92 (d, J = 4.3 Hz, 1H), 2.49 (dd, J = 13.6, 5.3 Hz, 2H),2.34-2.24 (m, 1H), 2.16-2.03 (m, 1H), 2.02-1.85 (m, 2H), 1.85-1.72 (m,2H), 1.76- 1.62 (m, 4H), 1.59 (s, 3H), 1.51- 1.42 (m, 6H), 1.14 (s, 3H),1.07- 0.99 (m, 1H) 25 Commercially available material

435 [M + H]⁺ 5.63 (s, 1H), 5.47 (d, J = 2.6 Hz, 1H), 5.13 (t, J = 7.4Hz, 1H), 4.05- 3.83 (m, 4H), 3.53 (dt, J = 19.3, 6.4 Hz, 3H), 3.39 (s,3H), 2.91 (d, J = 4.3 Hz, 1H), 2.54-2.44 (m, 4H), 2.35-2.24 (m, 1H),2.09 (dt, J = 14.7, 7.4 Hz, 1H), 1.97 (td, J = 13.5, 4.4 Hz, 1H),1.90-1.73 (m, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.12 (d, J = 6.2 Hz, 3H),1.00 (d, J = 13.6 Hz, 1H) 26 Commercially available material

463 [M + H]⁺ 5.51 (br, 1H), 5.14-5.19 (m, 1H), 3.54-3.57 (m, 1H),3.22-3.39 (m, 4H), 3.16-3.21 (m, 2H), 2.92-3.04 (m, 1H), 2.26-2.52 (m,5H), 1.84- 2.12 (m, 6H), 1.77-1.80 (m, 3H), 1.61-1.74 (m, 8H), 1.59 (s,3H), 1.45-1.58 (m, 3H), 1.18 (s, 3H), 0.98-1.02 (m, 1H) 27 Commerciallyavailable material

450 [M + H]⁺ 5.37-5.31 (m, 1H), 5.27-5.14 (m, 1H), 3.68-3.48 (m, 5H),3.36 (m, 2H), 3.31 (s, 3H), 3.20 (s, 2H), 2.86 (d, J = 4.4 Hz, 1H), 2.57(d, J = 4.4 Hz, 2H), 2.19 (m, 2H), 1.97 (m, 4.6 Hz, 1H), 1.89-1.67 (m,8H), 1.63 (s, 3H), 1.55-1.41 (m, 4H), 1.12 (s, 3H), 1.08 (m, 1H) 28Commercially available material

477 [M + H]⁺ 5.48 (d, J = 2.8 Hz, 1H), 5.18- 5.09 (m, 1H), 3.56 (dd, J =11.1, 2.7 Hz, 1H), 3.38 (s, 4H), 3.34 (d, J = 5.5 Hz, 3H), 2.92 (d, J =4.3 Hz, 1H), 2.49 (dd, J = 13.2, 5.4 Hz, 2H), 2.39 (s, 3H), 2.27 (s,3H), 2.14- 2.04 (m, 2H), 2.01-1.86 (m, 3H), 1.82-1.75 (m, 2H), 1.67 (s,3H), 1.59 (s, 3H), 1.53 (s, 4H), 1.36 (d, J = 47.3 Hz, 4H), 1.13 (d, J =6.5 Hz, 3H), 1.02 (dd, J = 11.2, 3.8 Hz, 1H) 29 Commercially availablematerial

463 [M + H]⁺ 5.52 (s, 1H), 5.50 (s, 1H), 5.14 (m, 1H), 3.61-3.43 (m,3H), 3.37 (s, 3H), 3.26 (m, 2H), 3.18-3.13 (m, 2H), 2.92 (d, J = 4.3 Hz,1H), 2.49 (m, 2H), 2.35-2.24 (m, 1H), 2.18 (m, 2H), 2.09 (m, 1H),2.02-1.87 (m, 2H), 1.84-1.74 (m, 2H), 1.67 (s, 3H), 1.58 (m, 7H), 1.13(m, 3H), 1.07-1.00 (m, 1H) 30 Commercially available material

477 [M + H]⁺ 5.49(s, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.60-3.40 (m, 5H),3.38 (d, J = 2.9 Hz, 3H), 3.32 (s, 4H), 2.92 (d, J = 4.3 Hz, 1H), 2.48(d, J = 4.4 Hz, 2H), 2.24 (s, 3H), 2.10 (s, 1H), 2.00- 1.88 (m, 2H),1.77 (dd, J = 12.3, 6.1 Hz, 5H), 1.67 (s, 4H), 1.59 (s, 3H), 1.14 (s,3H), 1.04 (d, J = 13.3 Hz, 1H) 31 Commercially available material

491 [M + H]⁺ 5.48 (s, 1H), 5.13 (m, 1H), 3.56 (dd, J = 11.1, 2.7 Hz,1H), 3.47 (s, 2H), 3.37 (s, 3H), 3.31-3.22 (m, 4H), 2.92 (d, J = 4.3 Hz,1H), 2.87 (s, 3H), 2.49 (m, 2H), 2.33-2.20 (m, 3H), 2.09 (m, 1H),2.00-1.88 (m, 2H), 2.01-1.87 (m, 2H), 1.85- 1.74 (m, 2H), 1.67 (m, 5H),1.59 (s, 3H), 1.41 m, 4H), 1.13 (s, 3H), 1.03 (d, J = 13.5 Hz, 1H) 32 14

449 [M + H]⁺ 5.51 (t, J = 7.1 Hz, 1H), 5.12 (d, J = 6.3 Hz, 1H),3.70-3.23 (m, 8H), 2.91 (t, J = 5.3 Hz, 1H), 2.74 (dd, J = 10.2, 4.6 Hz,3H), 2.62-2.47 (m, 2H), 2.34-2.20 (m, 1H), 2.04 (qdd, J = 17.3, 13.6,6.9 Hz, 3H), 1.91-1.71 (m, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.25 (t, J =3.0 Hz, 1H), 1.13 (s, 3H), 1.00 (d, J = 11.8 Hz, 1H) 33 15

463 [M + H]⁺ 5.49 (s, 1H), 5.19-5.07 (m, 1H), 3.66- 3.50 (m, 3H),3.49-3.39 (m, 2H), 3.39-3.33 (m, 3H), 3.08 (d, J = 20.6 Hz, 3H), 2.92(d, J = 4.3 Hz, 1H), 2.89 (s, 3H), 2.49 (dd, J = 10.4, 5.3 Hz, 2H),2.33-2.23 (m, 1H), 2.15-1.91 (m, 4H), 1.84 (ddd, J = 24.6, 10.8, 4.8 Hz,3H), 1.67 (d, J = 7.4 Hz, 3H), 1.59 (s, 3H), 1.20 (d, J = 12.2 Hz, 1H),1.13 (s, 3H), 1.01 (t, J = 12.2 Hz, 1H) 34 16

435 [M + H]⁺ 5.39-5.51 (m, 1H), 5.10-5.13 (m, 1H), 3.61-3.76 (m, 2H),3.52-3.57 (m, 2H), 3.36-3.38 (m, 1H), 3.37 (s, 3H), 2.90-2.92 (m, 1H),2.48-2.52 (m, 2H), 2.26-2.29 (m, 1H), 1.93- 2.12 (m, 4H), 1.72-1.85 (m,7H), 1.68 (s, 3H), 1.57 (s, 3H), 1.12 (s, 3H), 0.99-1.01 (m, 1H) 35 17

511 [M + H]⁺ 5.50 (s, 1H), 5.14 (t, J = 7.4 Hz, 1H), 4.67 (s, 1H), 4.48(d, J = 11.5 Hz, 1H), 4.24 (t, J = 12.1 Hz, 2H), 3.69-3.30 (m, 9H), 2.92(d, J = 4.3 Hz, 1H), 2.48 (t, J = 4.1 Hz, 2H), 2.28 (d, J = 7.0 Hz, 1H),2.16- 1.88 (m, 4H), 1.79 (dd, J = 20.6, 11.3 Hz, 3H), 1.68 (s, 3H), 1.59(s, 3H),1.34 (s, 1H), 1.13 (s, 3H), 1.00 (d, J = 13.3 Hz, 1H) 36 18

491 [M + H]⁺ 7.95 (s, 1H), 5.49 (s, 1H), 5.14 (s, 1H), 3.56 (ddd, J =11.3, 10.5, 7.2 Hz, 3H), 3.47 (dd, J = 21.0, 10.3 Hz, 2H), 3.41-3.36 (m,3H), 3.37- 3.15 (m, 4H), 2.92 (d, J = 4.3 Hz, 1H), 2.48 (d, J = 4.3 Hz,2H), 2.34- 2.24 (m, 1H), 2.10-1.97 (m, 3H), 1.81 (dd, J = 19.3, 8.2 Hz,3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.15 (q, J = 6.7 Hz, 7H), 1.06 (dd, J =20.1, 16.8 Hz, 5H) 37 19

548 [M + H]⁺ 5.49 (s, 1H), 5.13 (s, 1H), 3.86- 3.74 (m, 6H), 3.68-3.44(m, 5H), 3.39 (dd, J = 11.1, 3.7 Hz, 5H), 2.91 (d, J = 4.3 Hz, 1H), 2.80(d, J = 4.4 Hz, 2H), 2.64 (d, J = 5.6 Hz, 3H), 2.48 (d, J = 4.2 Hz, 2H),2.28 (d, J = 7.2 Hz, 1H), 2.13-1.86 (m, 5H), 1.79 (d, J = 5.4 Hz, 2H),1.68 (s, 3H), 1.59 (s, 3H), 1.13 (s, 3H), 1.01 (s, 1H) 38 20

562 [M + H]⁺ 5.49 (s, 1H), 5.14 (t, J = 7.4 Hz, 1H), 3.86-3.31 (m, 14H),3.12 (d, J = 14.1 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.50 (tt, J = 24.4,12.2 Hz, 7H), 2.33-2.23 (m, 1H), 2.16- 1.92 (m, 4H), 1.89-1.73 (m, 3H),1.68 (s, 3H), 1.64-1.54 (m, 4H), 1.12 (d, J = 6.0 Hz, 3H), 1.04- 0.95(m, 1H) 39 21

497 [M + H]⁺ 5.46 (s, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.95-3.22 (m, 12H),2.92 (d, J = 4.3 Hz, 1H), 2.69-2.34 (m, 4H), 2.28 (dd, J = 14.3, 7.0 Hz,1H), 2.09 (dt, J = 14.6, 7.2 Hz, 1H), 2.03-1.91 (m, 1H), 1.86 (d, J =14.8 Hz, 1H), 1.81-1.71 (m, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.40 (d, J= 27.9 Hz, 2H), 1.12 (d, J = 6.1 Hz, 3H), 1.09-0.95 (m, 1H), 0.68-0.62(m,1H) 40 22

491 [M + H]⁺ 5.45 (d, J = 10.1 Hz, 1H), 5.18- 5.09 (m, 1H), 3.71 (d, J =18.5 Hz, 4H), 3.65-3.48 (m, 3H), 3.44 (s, 1H), 3.39-3.24 (m, 5H), 2.91(d, J = 4.3 Hz, 1H), 2.69-2.34 (m, 6H), 2.28 (dt, J = 13.0, 6.5 Hz, 3H),2.08 (dt, J = 22.2, 7.4 Hz, 1H), 2.02- 1.72 (m, 5H), 1.68 (s, 3H), 1.59(s, 3H), 1.13 (s, 3H), 1.00 (dd, J = 13.5, 2.4 Hz, 1H), 0.81-0.63 (m,1H) 41 23

477 [M + H]⁺ 5.45 (d, J = 8.0 Hz, 1H), 5.18- 5.10 (m, 1H), 3.57 (dd, J =11.1, 3.1 Hz, 2H), 3.44 (s, 1H), 3.40-3.31 (m, 4H), 2.91 (d, J = 4.3 Hz,1H), 2.69-2.24 (m, 9H), 2.15-1.71 (m, 6H), 1.68 (s, 3H), 1.59 (s, 3H),1.35 (d, J = 28.5 Hz, 2H), 1.13 (d, J = 1.4 Hz, 3H), 1.01 (dt, J = 23.6,7.0 Hz, 7H), 0.72 (ddd, J = 40.2, 6.7, 3.3 Hz, 1H) 42 24

479 [M + H]⁺ 5.50(s, 1H), 5.14 (t, J = 7.5 Hz, 1H), 3.64-3.62 (m, 4H),3.58- 3.54 (m, 4H),3.39 (s, 3H), 3.26- 3.21 (m, 4H), 2.92 (d, J = 4.3Hz, 1H), 2.81 (s, 2H), 2.51-2.47(m, 2H), 2.38-2.21 (m, 1H), 2.14- 2.04(m, 1H), 2.03-1.84 (m, 2H), 1.80-1.79 (m, 3H), 1.68 (s, 3H), 1.59 (s,3H), 1.13 (s, 3H), 1.02 (d, J = 12.6 Hz, 1H) 43 25

492 [M + H]⁺ 5.50 (s, 1H), 5.14 (m, 1H), 3.65- 3.48 (m, 5H), 3.39 (s,3H), 3.28- 3.07 (m, 4H), 2.92 (d, J = 4.3 Hz, 1H), 2.77 (d, J = 8.9 Hz,8H), 2.49 (m, 2H), 2.33-2.25 (m, 1H), 2.09 (m, 1H), 2.02-1.96 (m, 1H),1.90 m, 1H), 1.79 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.14 (s, 3H),1.01 (d, J = 13.5 Hz, 1H) 44 26

492 [M + H]⁺ 5.50 (s, 1H), 5.14 (m, 1H), 4.05 (m, 1H), 3.50 (m, 4H),3.38 (m, 3H), 3.34-3.07 (m, 6H), 2.92 (d, J = 4.1 Hz, 1H), 2.85 (s, 2H),2.51-2.47 (m, 1H), 2.35-2.22 (m, 1H), 2.15- 1.94 (m, 3H), 1.89 (d, J =12.3 Hz, 1H), 1.82-1.72 (m, 2H), 1.68 (s, 3H), 1.59 (s, 4H), 1.12 (s,3H), 1.08 (m, 3H), 1.01 (d, J = 13.5 Hz, 1H) 45 27

478 [M + H]⁺ 5.49 (s, 1H), 5.14 (m, 1H), 4.10 (s, 1H), 3.71-3.41 (m,5H), 3.37 (m, 3H), 3.26 (m, 3H), 3.16-3.06 (m, 1H), 2.92 (d, J = 4.3 Hz,1H), 2.89- 2.78 (m, 2H), 2.74 (s, 3H), 2.49 (m, 2H), 2.34-2.24 (m, 1H),2.09 (m, 1H), 1.99 (m, 1H), 1.89 (dd, J = 14.2, 2.1 Hz, 1H), 1.83-1.74(m, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.12 (s, 3H), 1.01 (d, J = 11.5 Hz,1H) 46 28

491 [M + H]⁺ 5.50 (s, 1H), 5.18-5.08 (m, 1H), 3.75-3.52 (m, 5H), 3.40(d, J = 8.1 Hz, 3H), 3.37 (d, J = 7.3 Hz, 1H), 3.31 (ddd, J = 17.2,10.4, 4.2 Hz, 2H), 3.22-3.04 (m, 1H), 2.97- 2.74 (m, 3H), 2.62-2.52 (m,1H), 2.51-2.45 (m, 2H), 2.33-2.24 (m, 1H), 2.16-2.05 (m, 1H), 1.99 (td,J = 13.8, 4.2 Hz, 1H), 1.88 (d, J = 13.9 Hz, 1H), 1.79 (d, J = 11.3 Hz,2H), 1.68 (s, 4H), 1.59 (s, 3H), 1.14 (s, 3H), 1.05 (dd, J = 6.6, 3.3Hz, 6H) 47 29

477 [M + H]⁺ 5.48 (d, J = 15.7 Hz, 1H), 5.14 (t, J = 7.4 Hz, 1H),3.72-3.53 (m, 5H), 3.39 (s, 3H), 3.38 (s, 1H), 3.30- 3.23 (m, 2H), 3.13(ddd, J = 27.4, 13.6, 8.1 Hz, 1H), 2.92 (d, J = 4.1 Hz, 1H), 2.81 (d, J= 5.3 Hz, 2H), 2.53-2.44 (m, 2H), 2.33-2.25 (m, 1H), 2.24-2.15 (m, 2H),2.15- 2.05 (m, 1H), 2.03-1.94 (m, 1H), 1.90 (s, 1H), 1.79 (d, J = 11.4Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.18 (s, 1H), 1.14 (s, 3H), 1.09(dd, J = 13.1, 5.7 Hz, 3H) 48 30

534 [M + H]⁺ 5.48 (s, 1H), 5.14 (s, 1H), 3.75- 3.08 (m, 14H), 2.92-2.82(m, 3H), 2.74-2.40 (m, 5H), 2.31-2.25 (m, 1 H), 2.17-1.94 (m, 3H), 1.93-1.73 (m, 5H), 1.68 (s, 3H), 1.27- 0.97 (m, 10H), 0.80 (d, J = 7.0 Hz,1H) 49 31

548 [M + H]⁺ 5.49 (s, 1H), 5.13 (s, 1H), 3.76- 3.26 (m, 17H), 3.28-3.03(m, 2H), 2.92-2.68 (m, 3H), 2.62-2.47 (m, 4H), 2.30-2.25 (m, 1H),2.17-1.95 (m, 3H), 1.91-1.78 (m, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.19(m, 5H), 1.01 (d, J = 13.6 Hz, 1H), 0.81 (t, J = 6.8 Hz, 1H) 50 32

479 [M + H]⁺ 5.42-5.46 (m, 1H), 5.12-5.16 (m, 1H), 4.53-4.62 (m, 1H),3.82-3.95 (m, 2H), 3.53-3.60 (m, 2H), 3.23- 3.44 (m, 6H), 2.91 (d, J =4.8 Hz, 1H), 2.72-2.74 (m, 3H), 2.46-2.52 (m, 2H), 2.28-2.32 (m, 1H),2.06- 2.12 (m, 1H), 1.79-2.01 (m, 4H), 1.75 (s, 3H), 1.60 (s, 3H),1.40-1.45 (m, 2H), 1.19 (s, 3H), 0.85-0.95 (m, 2H) 51 33

493 [M + H]⁺ 5.42-5.47 (m, 1H), 5.12-5.16 (m, 1H), 3.92-3.97 (m, 1H),3.79-3.85 (m, 1H), 3.51-3.62 (m, 2H), 3.41- 3.44 (m, 1H), 3.29-3.37 (m,5H), 2.90 (d, J = 4.4 Hz, 1H), 2.84-2.86 (m, 6H), 2.46-2.51 (m, 2H),2.26- 2.28 (m, 1H), 1.71-2.15 (m, 5H), 1.68 (s, 3H), 1.61 (s, 3H),1.41-1.47 (m, 2H), 1.14-1.18 (m, 3H), 0.91- 1.05 (m, 2H) 52 34

505 [M + H]⁺ 5.42 (d, J = 3.0 Hz, 1H), 5.20- 5.10 (m, 1H), 4.17-3.65 (m,8H), 3.53 (m, 1H), 3.37 (s, 3H), 2.91 (d, J = 4.3 Hz, 1H), 2.53-2.23 (m,11H), 2.09 (m, 1H), 2.02-1.93 (m, 1H), 1.89-1.70 (m, 6H), 1.68 (s, 3H),1.59 (s, 3H), 1.12 (s, 3H), 0.99 (m, 1H)

Following the above procedures, the following compounds are prepared:

Example Structure 53

54

55

56

57

58

59

60

61

Biological Example A

Compounds are tested for their capacity to inhibit recombinant humanMetAP2 activity using the following assay.

Flag tagged Human recombinant MetAP2 expressed and isolated for use asthe enzyme source. 10 mM stock solutions of compounds were prepared in100% DMSO and further diluted in 100% DMSO required concentration to 1mM stocks. The stock compound solutions and DMSO vehicle controls werediluted to target final compound concentrations using assay buffer to afinal concentration of 50 mM HEPES containing 100 mM NaCl, pH adjustedto 7.5. The MAS peptide was formulated to a 7.5 mM stock in distilledwater and prior to use further diluted 1:4. Amino acid oxidase wasprepared as a stock solution (6.2 mg/ml) and prior to use furtherdiluted 1:49.6 in distilled water. A 250 μM solution of MnCl₂ wasprepared in advance of thawing an aliquot of MetAP2 enzyme. 40 μl ofenzyme was mixed with 100 μl of MnCl₂ then further diluted in assaybuffer to a final concentration of 16 μg/ml. To test for compound effecton MetAP2 enzyme activity, 5 μl of test compound, 10 μl of MASsubstrate/amino acid oxidase mixture, 10 μl of MetAP2 was added to testwells in a 384 well black plate with blank wells containing no enzyme,replaced with 10 μl of assay buffer. All compounds were tested induplicate on two occasions on the same day. The final in wellconcentrations of the assay were: 1% DMSO, 0.272 μg/ml MetAP2, 10 μMMnCl₂, 50.0 μg/ml (0.225 U/ml) amino acid oxidase, and 0.0.75 mM MAS.

The plate was sealed with a TopSeal A cover and mixed briefly on anorbital mixer at 900 rpm. The plate was incubated for a further 25minutes at 25° C. A 5× stock of Amplex buffer was prepared (0.25M sodiumphosphate, pH 7.4) and stored at 4° C. When preparing for use the stockwas diluted with distilled water. Amplex Ultraread stock solution wasprepared at 2.57 mg/ml in 100% DMSO and stored in 50 μl aliquots at −20°C. 20 μl of 505 U/ml. Horse radish peroxidase was diluted in 990 ml ofAmplex buffer, 100 μl of this was combined with 50 μl of Amplex Ultraredin 4850 ml of 1× Amplex buffer to generate sufficient detection reagentfor a 384 well plate. 25 μl detection reagent was added to each well ofthe test plate, which was re-sealed and mixed briefly on an orbitalshaker. The plate was transferred to an Envision Multi-label reader andRFU measured corresponding to excitation 531 nm and emission 595 nm. Atthe end of the MetAP2 incubation 25 μl Amplex/HRP mixture per well wasadded and the plate read plate on a plate reader.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control.

Compounds of the disclosure demonstrated activity in the assay of thisExample as indicated in the following tables, wherein A represents anIC₅₀ of <0.05 μM and B represents an IC₅₀ between 0.05 μM and 0.5 μM.

TABLE 1 Example No. Compound Name MetAP2 IC₅₀ (μM) 1(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Benyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate 2(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate 8(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate formate 11(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-methyl-6-azaspiro[3.4]octan-2-ylcarbamate formate 10(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-methyl-2-azaspiro[3.3]heptan-6-ylcarbamate formate 7(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-methyl-7-azaspiro[3.5]nonan-2-ylcarbamate formate 20(3aR,6aS)-((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- Amethylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate formate 26(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate 12(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate 22(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate 23(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Benyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-thia-6-azaspiro[3.3]heptane2,2-dioxide-6-carboxylate 27(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Benyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-oxa-2-azaspiro[4.5]decane-2-carboxylate 9(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Benyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate formate 4(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate formate 5(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate 3(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-oxa-2-azaspiro[3.5]nonane-2-carboxylate 24(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Benyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate 6(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate 19(3aR,6aS)-((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- Bmethylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 32(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- Bmethylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 33(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- Bmethylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 34(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3- Amethylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate 25(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2- Aenyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate compound A[(3R,6R,7S,8S)-7-methoxy-8-[(2R,3R)-2-methyl-3-(3-methylbut- B2-enyl)oxiran-2-yl]-2-oxaspiro[2.5]octan-6-yl] (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]prop-2-enoate

Biological Example B Study Summary Mouse DIO:

The objective of this study design was to investigate the efficacy ofdisclosed compounds in a 10 day DIO mouse model. Effects on body weight,food intake, hematology and blood chemistry were the primary readouts ofthis study design. Male, Diet Induced Obese (DIO) C57BL/6 mice, 19-21weeks of age (13-15 weeks on high fat diet) were ordered from acertified vendor and upon receipt were housed on irradiated corncobbedding in micro-isolator cages on a 12-hour light-dark cycle(0700-1900) at 68-74° F. and 30-70% humidity. Mice were fed ResearchDiets D12492 (60% Kcal fat, 20% Kcal carbohydrate and 20% protein) andprovided water ad libitum. DIO mice were received and housed in thefacility for approximately two weeks prior to the start of test articleadministration. On Day −4 or −3, mice were randomized into study groupsbased on body weight and body weights were continued to be recordeddaily for the duration of the study. Daily food intake was assessedstarting on Study Day −2 by weighing of the food with hopper together toavoid loss of food in transfer.

Compounds were formulated into a 100% DMSO stock (at 9 mg/mL) prior tothe start, and further diluted into the target working concentrationusing the vehicle of 10% DMSO in water. Prior to test articleadministration, starting on Day −3 a dosing acclimation occurred withall animals receiving a subcutaneous injection of vehicle (10% DMSO)only for 3 days. Starting on Day 1, test compounds or vehicle wereadministered based on individual body weight, subcutaneously, once a dayfor 10 days. All mice were sacrificed on Day 11, 24 hours following thefinal dosing on Day 10. After sacrifice, whole blood was collected andanalyzed for hematology and blood chemistry parameters.

Study Summary Rat DIO:

The objective of this study design is to investigate the efficacy ofdisclosed compounds in an 11 day rat DIO model used to screen compoundsfor pharmacologic efficacy on endpoints related to obesity andmetabolism. Effects on body weight, food intake, hematology and bloodchemistries were the primary readouts of this study design. Male SpragueDawley rats, approximately 8 weeks of age, were ordered from a certifiedvendor and housed on irradiated corncob bedding in micro-isolator cages,on a 12-hour light-dark cycle (0700-1900) at 68-74° F. and 30-70%humidity. Rats were fed Research Diets D12451 (45% High Fat) andprovided water ad libitum. Rats were received and housed in the facilityfor at least two or three weeks prior to start of test articleadministration. On Day −4 or −3, rats were randomized into study groupsbased on body weight and body weights were continued to be recordeddaily for the duration of the study. Daily food intake was assessedstarting on Study Day −2 by weighing the hopper including the food toavoid loss of food in transfer.

Compounds were formulated into a 100% DMSO stock (at 9 mg/mL) prior tothe start, and further diluted into the target working concentrationusing the vehicle of 10% DMSO in water. Prior to test articleadministration, starting on Day −3 a dosing acclimation occurred withall animals receiving a subcutaneous injection of vehicle (10% DMSO)only for 3 days. Starting on Day 1, test compounds or vehicle wereadministered based on individual body weight, subcutaneously, once a dayfor 11 days. All animals were sacrificed on Day 11, approximately 2hours following the final dosing on Day 11. After sacrifice, whole bloodwas collected and analyzed for hematology and blood chemistryparameters.

Compounds were tested for weight loss vs. vehicle at 0.3 and 1.0 mpk sc(mg per kg animal weight delivered subcutaneously), and the results areshown in Table 2 below.

TABLE 2 Mouse @ Rat @ 0.3 Ra @ 1.0 0.3 mpk sc mpk sc mpk sc Example No.Compound Name (%) (%) (%) 1 (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-17 10.3 16.3 3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-oxa-9- azaspiro[5.5]undecane-9-carboxylate 2(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 11.1 8 10.23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate 8(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 6.23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl7-methyl-2,7- diazaspiro[3.5]nonane-2-carboxylate formate 11(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 63-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl6-methyl-6- azaspiro[3.4]octan-2-ylcarbamate formate 10(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 8.4 2 7.23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl2-methyl-2- azaspiro[3.3]heptan-6-ylcarbamate formate 7(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 1.93-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl7-methyl-7- azaspiro[3.5]nonan-2-ylcarbamate formate 20(3aR,6aS)-((3R,4S,5S,6R)-5-methoxy-4- 1.4((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate formate 26(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 5.63-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl8-methyl-2,8- diazaspiro[4.5]decane-2-carboxylate 12(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 1.83-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl6-methyl-2,6- diazaspiro[3.3]heptane-2-carboxylate 22(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 15.53-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl6,6-difluoro-3- azabicyclo[3.1.0]hexane-3-carboxylate 23(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide-6-carboxylate 27(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 16.33-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 8-oxa-2-azaspiro[4.5]decane-2-carboxylate 9(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 21.53-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl7-(2,2-difluoroethyl)- 2,7-diazaspiro[3.5]nonane-2-carboxylate formate 4(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 15.43-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate formate 5(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 16.7 6.63-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate 3(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 18.9 7.93-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 7-oxa-2-azaspiro[3.5]nonane-2-carboxylate 13(3aR,6aS)-((3R,4S,5S,6R)-5-methoxy-4- 16.9 3.1((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl)tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- carboxylate 24(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 20.5 6.33-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate 6(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 13.9 2.73-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate 19(3aR,6aS)-((3R,4S,5S,6R)-5-methoxy-4- 22.6 7.6((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate 32(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4- 4((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate 33(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4- 13.8((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate 37(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4- 4.3((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-((2-morpholinoethyl)carbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate 34(1R,5S,6R)-(3R,4S,5S,6R)-5-methoxy-4- 3((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3- carboxylate 14(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 23.3 11.63-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl9-(2,2-difluoroethyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate 25(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate 29(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- −0.53-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate 40(1R,5S,6S)-((3R,4S,5S,6R)-5-methoxy-4- 11.1((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate 30(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 1.13-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate 28(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 83-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl9-methyl-3,9- diazaspiro[5.5]undecane-3-carboxylate 31(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 3.63-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl9-methyl-8-oxo-3,9- diazaspiro[5.5]undecane-3-carboxylate 15(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 22.53-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl2-(2,2-difluoroethyl)- 2,6-diazaspiro[3.4]octane-6-carboxylate 21(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 21.23-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl 3-azabicyclo[3.1.0]hexane-3-carboxylate 16(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl- 23.43-(3-methylbut-2-enyl)oxiran-2-yl)-1- oxaspiro[2.5]octan-6-yl8-(2,2-difluoroethyl)- 2,8-diazaspiro[4.5]decane-2-carboxylate 42(3aR,6aS)-2-((3R,4S,5S,6R)-5-methoxy-4- 12.4((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5- methyltetrahydropyrrolo[3,4-c]pyrrole- 2,5(1H,3H)-dicarboxylate compound[(3R,6R,7S,8S)-7-methoxy-8-[(2R,3R)-2-methyl- 18.0 20.0 A3-(3-methylbut-2-enyl)oxiran-2-yl]-2-oxaspiro[2.5]octan-6-yl](E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]prop-2-enoate

Biological Example C Study Summary HT-1080:

The human fibrosarcoma cell line HT-1080 were grown to almost completeconfluence in T75 tissue culture flasks in preparation for theexperiment. The cells were trypsinised and re-suspended in completemedium using DMEM plus 9% FBS including penicillin/streptomycinsupplements. 500 cells in a total volume of 25 μl were seeded into blackwalled 384 well plates and returned to a CO2 incubator over-night.Compounds and standards were prepared at 333.3× actual testconcentration in neat DMSO. 10 point dose response curves of testcompounds were generated by 1:3 serial dilutions, 2 μl of DMSO stock wastransferred to 109 μl complete medium. This was further diluted 1:6 incomplete medium, with 5 μl of the resulting solution added to theincubated 384 well plate. The assay had a final DMSO concentration of0.3%, a level which was identified as being non-cytotoxic to the cells.For experimental blanks at the start of the experiment, CellTiter-Glowas added to a satellite plate of cells (identical to the experimentalplate), when adding compounds on Day 1. The average of these wells isused as the blanks in the calculation template. Following 72 hoursincubation with compounds and standard the plate was removed from theincubator and allowed to equilibrate at room temperature for at least 30minutes. CellTiter-Glo was thawed and subsequently 30 μl added tocolumns 2-23. The plate was covered with a clear Perkin Elmer Topsealand placed on a plate shaker for 10-20 mins to aid homogenous mixing.Luminescence per well was determined using an EnVision 2104 MultilabelReader (PerkinElmer) or other suitable reader. The compound blank valuerecorded on Day 1 is subtracted from all other data. Data is expressedas % inhibition of mean DMSO control response and the EC₅₀ is calculatedas 50% maximum response. The EC₅₀ values are determined from a sigmoidal4 parameter curve fit using XLfit in conjunction with Activity Base(IDBS; Guildford, Surrey, UK). The bottom of the curve is fixed to 0%inhibition.

Study Summary Rat Embryofetal:

The objective of this study design was to evaluate the potential effectsof disclosed compounds on embryo/fetal development when givensubcutaneously to pregnant rats once every three days during thecritical period of organogenesis (Gestation Days 6-18). Female, SpragueDawley rats, approximately 10 weeks of age, time bred, were ordered froma certified vendor and housed individually housed in stainless steelcages suspended over flush pans, on a 12-hour light-dark cycle(0700-1900) at 20-26° C. and 30-70% humidity. Rats were fed a standardrodent chow and provided water ad libitum. Rats were received and housedin the facility for a period of approximately 1 to 2 days.

Compounds were formulated using 100% DMSO mixed in Sterile Water forInjection, resulting in 2% DMSO solution in water. If necessary, due tolimited solubility of a test article, a higher percentage of DMSOsolution in water was used. Groups of 8 mated and presumed pregnantfemale rats were given subcutaneous doses of vehicle or test article,once every three days, beginning on Gestation Day 6 and ending onGestation Day 18 (Days 6, 9, 12, 15, and 18), maintained two more days,and then euthanized and necropsied on Gestation Day 20. Body weights wasrecorded for all animals on Gestation Days 5 (purpose of randomization),6, 9, 12, 15, 18, and 20 (scheduled euthanasia). Food consumption byweight was recorded on Gestation Days 6, 9, 12, 15, 18, and 20(scheduled termination).

At necropsy, the dams were examined visually for external abnormalitiesincluding palpable masses. The abdominal, thoracic, and cranial cavitiesand their contents were examined for abnormalities and findings will berecorded. The reproductive tract were examined to record the number ofovarian corpora lutea, the number and location of uterine implantationsites noting the position of the cervix, and the number of earlyresorptions, late resorptions, live fetuses, and dead fetuses. For deadfetuses and late resorptions, crown-to-rump length and weight wererecorded, if possible, and the fetus was discarded. For viable fetuses,weight, sex, and grossly visible external abnormalities were recorded.Fetuses with external findings involving the head had a fresh visceralevaluation performed on the head to confirm the external finding, ifapplicable.

The results are summarized in Table 3, below, wherein A represents anEC₅₀ of <0.50 nM and B represents an EC₅₀ between 0.50 nM and 1.0 nM.

TABLE 3 HT-1080 Rat EC50 Embryofetal Example (nM) @6 mpk 2 A Positive 22A Negative 27 A Positive 9 A Positive 4 A Negative compound A B Positive

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety for all purposes as if each individualpublication or patent was specifically and individually incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the present disclosure will become apparent to thoseskilled in the art upon review of this specification. The full scope ofthe disclosure should be determined by reference to the claims, alongwith their full scope of equivalents, and the specification, along withsuch variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

What is claimed is:
 1. A compound represented by:

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable excipient. 3.The composition of claim 2, wherein the composition is formulated as aunit dose.
 4. The composition of claim 2, wherein the composition isformulated for subcutaneous administration.
 5. The composition of claim2, wherein the composition is formulated for intravenous administration.